research topics ovarian cancer

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Ovarian cancer: New treatments and research

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By Nicole Brudos Ferrara

Three cancers — ovarian epithelial cancer, fallopian tube cancer and primary peritoneal cancer — are commonly called ovarian cancer. They arise from the same kind of tissue and are treated similarly.

"The ovaries and fallopian tubes are so anatomically close to each other that we sometimes can't tell if the cancer is coming from the ovary or the fallopian tube," says S. John Weroha, M.D., Ph.D. , a Mayo Clinic oncologist and chair of Mayo Clinic Comprehensive Cancer Center's Gynecologic Cancer Disease Group. "When we diagnose patients with primary peritoneal cancer, I explain that under the microscope, and in the pattern of spread through the body, it looks like ovarian cancer even though the ovaries are not involved."

Primary peritoneal cancer forms in the peritoneum, the tissue that lines the abdominal cavity and the organs within it. Fallopian tube cancer forms in the tissue lining the inside of the tubes that eggs travel through to move from the ovaries to the uterus.

About 85% to 90% of ovarian cancers are ovarian epithelial cancers, also known as epithelial ovarian carcinomas, which form in the tissue lining the outside of the ovaries.

Dr. Weroha says new treatments are helping more people survive ovarian cancer of all types, and researchers are studying new treatments and screening methods in clinical trials. If you've been diagnosed with ovarian cancer, he wants you to know there is hope. Here's why:

New targeted therapies are improving survival.

Surgery and chemotherapy are no longer the only options for ovarian cancer treatment . Targeted therapies use drugs to target and attack cancer cells. These include monoclonal antibodies and poly (ADP-ribose) polymerase, or PARP, inhibitors.

Monoclonal antibodies

Monoclonal antibodies are molecules engineered in the laboratory to find and attach to specific proteins associated with cancer cells. Bevacizumab is a monoclonal antibody used with chemotherapy to treat ovarian cancer recurrence by preventing the growth of new blood vessels that tumors need to grow.

Researchers are combining bevacizumab with new drugs to improve outcomes. One example is a monoclonal antibody recently approved by the Food and Drug Administration (FDA) called mirvetuximab soravtansine for people with ovarian cancer recurrence. This drug is used when a person's cancer was previously treated with at least one systemic therapy to target a protein called folate receptor alpha.

"Ovarian cancers have many folate receptors. Most normal cells don't," says Dr. Weroha. "This drug is an antibody that has chemotherapy stuck onto it. Think of it as a guided missile traveling the body and sticking to cells with folate receptors. In patients whose ovarian cancer has recurred and whose tumors have many folate receptors, mirvetuximab soravtansine can shrink tumors far better than any other therapy. The response rate is about double what you see with any other treatment."

PARP inhibitors

PARP inhibitors are drugs that block DNA repair, which may cause cancer cells to die. Olaparib is an example of a PARP inhibitor used to prevent recurrence in people with ovarian cancer whose tumors have BRCA1 or BRCA2 gene mutations. Research has shown that olaparib can significantly improve survival without recurrence in people with this diagnosis. "This is a front-line treatment, which means this is part of the first treatment regimen patients receive when they are newly diagnosed," says Dr. Weroha.

A vaccine may one day be used to fight ovarian cancer.

Matthew Block, M.D., Ph.D. , a Mayo Clinic medical oncologist, and Keith Knutson, Ph.D. , a Mayo Clinic researcher, are developing a vaccine to prevent ovarian cancer tumors from returning in people with advanced ovarian cancer whose tumors have recurred after surgery and chemotherapy.

White blood cells are extracted from a blood draw and manufactured to become dendritic cells — immune cells that boost immune responses. These cells are returned to the patient in vaccine form to trigger the immune system to recognize and fight the cancer.

The vaccine will be given in combination with an immunotherapy drug called pembrolizumab to identify and kill any tumors that don't respond to the dendritic cells.

"Pembrolizumab is in a category of drugs called immune checkpoint inhibitors ," says Dr. Weroha. "This drug is designed to release the brakes on the immune system to allow it to do what it naturally wants: kill things it doesn't like. The hope is that the vaccine combined with the immunotherapy drug will kill a lot of ovarian cancer. It's exciting research."

A screening test may be on the horizon.

There is no screening test for ovarian cancer, but Jamie Bakkum-Gamez, M.D. , a Mayo Clinic gynecologic oncologist, is hoping to change that. She and her research team discovered that methylated DNA markers could be used to identify endometrial cancer through vaginal fluid collected with a tampon. Eventually, this same science could extend to ovarian cancer.

Methylation is a mechanism cells use to control gene expression — the process by which a gene is switched on in a cell to make RNA and proteins. When a certain area of a gene's DNA is methylated, the gene is turned off or silenced, indicating that a gene is a tumor suppressor. The silencing of tumor suppressor genes is often an early step in cancer development and can suggest cancer.

Dr. Bakkum-Gamez and her colleagues developed a panel of methylated DNA markers that could distinguish between endometrial cancer and noncancerous tissue in vaginal fluid. Based on this research, she hopes to develop an affordable tampon-based home screening test for endometrial, ovarian and cervical cancers, as well as high-risk HPV .

"This is exciting because this type of screening test can be used by people living in rural areas,” says Dr. Weroha. “If it's successful, it could help healthcare professionals identify ovarian and other gynecologic cancers sooner, when they're more treatable, in people living in all the communities we serve.”

A gynecologic oncologist and clinical trials can help you get the best possible treatment.

If you've been diagnosed with ovarian cancer, Dr. Weroha recommends making an appointment with a gynecologic oncologist . "A gynecologic oncologist will be up to date on the current treatment recommendations and the management of side effects. That's important," he says. "Once the plan is set, however, any medical oncologist could implement it.”

Dr. Weroha also recommends newly diagnosed patients ask their care teams if they are candidates for PARP inhibitors, mirvetuximab or clinical trials. "PARP inhibitors and mirvetuximab are newer treatments that could influence the outcome of your overall treatment. Always ask about clinical trials because when ovarian cancer recurs, there is no treatment so good that we can stop looking for something better," he says. "There is a very realistic hope that if your cancer were to come back, we would have something better that we don't have today."

Learn more about ovarian cancer and find a clinical trial at Mayo Clinic.

Join the Gynecologic Cancers Support Group on Mayo Clinic Connect , an online community moderated by Mayo Clinic for patients and caregivers.

Join the next virtual Gynecologic Cancer Support Meeting: Women of S-Teal . Monthly meetings are held every second Monday from 5:30 to 6:30 p.m. ET.

Also, read these articles:

• A step toward detecting endometrial cancer earlier
• Harnessing the immune system to fight ovarian cancer
• Life after ovarian cancer: Coping with side effects, fear of recurrence, and finding support
• New surgical method for ovarian cancer lights up lesions
• Is a cancer clinical trial right for me?
• New chemotherapy approach for late-stage cancers

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Dr. Brad Nitzsche explains why there isn't a universal screening program for ovarian cancer and the symptoms to watch for.

Dr. Maria Linnaus discusses the link between obesity and cancer risk and how bariatric surgery may reduce that risk.

Dr. Kristina Butler discusses health disparities in cancers of the ovaries, uterus, cervix, vulva and vagina and makes recommendations for prevention.

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Recent Advances in Ovarian Cancer: Therapeutic Strategies, Potential Biomarkers, and Technological Improvements

Salima akter.

1 Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Korea; db.ca.shub@5102_amilas (S.A.); rk.ca.uhk@23030caj (Y.S.); rk.ca.uhk@naheehnus (S.H.); rk.ca.uhk@gnaksi (I.K.); rk.ca.uhk@hjah (J.H.); rk.ca.uhk@eohcw (W.C.)

2 Biomedical Science Institute, Kyung Hee University, Seoul 02447, Korea

3 Department of Medical Biotechnology, Bangladesh University of Health Sciences, Dhaka 1216, Bangladesh; moc.liamg@9051egbayirp

Md. Ataur Rahman

4 Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea; rk.ca.uhk@32namhar (M.A.R.); rk.ca.uhk@mikeelgnob (B.K.)

5 Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea

6 Global Biotechnology & Biomedical Research Network (GBBRN), Department of Biotechnology and Genetic Engineering, Faculty of Biological Sciences, Islamic University, Kushtia 7003, Bangladesh

Mohammad Nazmul Hasan

7 Pristine Pharmaceuticals, Patuakhali 8600, Bangladesh; moc.liamg@egbnibon

Hajara Akhter

8 Biomedical and Toxicological Research Institute, Bangladesh Council of Scientific and Industrial Research (BCSIR), Dhaka 1205, Bangladesh; db.vog.riscb@arajah

Rokibul Islam

9 Department of Biotechnology and Genetic Engineering, Faculty of Biological Sciences, Islamic University, Kushtia 7003, Bangladesh; db.ca.ui.egtb@malsirm

10 Department of Biochemistry, College of Medicine, Hallym University, Chuncheon 24252, Korea

Yoonhwa Shin

11 Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Korea; rk.ca.uhk@806kcc

MD. Hasanur Rahman

12 Department of Biotechnology and Genetic Engineering, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj 8100, Bangladesh; [email protected]

Md. Shamim Gazi

13 Biotechnology and Genetic Engineering Discipline, Khulna University, Khulna 9208, Bangladesh; db.ca.uk@egbizagmimahs

Md Nazmul Huda

14 Department of Biochemistry and Molecular Biology, UAMS Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences UAMS, Little Rock, AR 72205, USA; ude.smau@aduhnm

Nguyen Minh Nam

15 Research Center for Genetics and Reproductive Health, School of Medicine, Vietnam National University Ho Chi Minh City, Linh Trung Ward, Thu Duc District, Ho Chi Minh City 71308, Vietnam; nv.ude.unvdem@manmn

Jinwook Chung

Bonglee kim, wonchae choe, tae gyu choi, sung soo kim, associated data.

Not applicable.

Aggressive and recurrent gynecological cancers are associated with worse prognosis and a lack of effective therapeutic response. Ovarian cancer (OC) patients are often diagnosed in advanced stages, when drug resistance, angiogenesis, relapse, and metastasis impact survival outcomes. Currently, surgical debulking, radiotherapy, and/or chemotherapy remain the mainstream treatment modalities; however, patients suffer unwanted side effects and drug resistance in the absence of targeted therapies. Hence, it is urgent to decipher the complex disease biology and identify potential biomarkers, which could greatly contribute to making an early diagnosis or predicting the response to specific therapies. This review aims to critically discuss the current therapeutic strategies for OC, novel drug-delivery systems, and potential biomarkers in the context of genetics and molecular research. It emphasizes how the understanding of disease biology is related to the advancement of technology, enabling the exploration of novel biomarkers that may be able to provide more accurate diagnosis and prognosis, which would effectively translate into targeted therapies, ultimately improving patients’ overall survival and quality of life.

1. Introduction

Ovarian cancer (OC) is the presence of abnormal cells that initially grow in the ovary and then reproduce out of control, which can form a tumor malignancy when they spread into the surrounding tissues [ 1 , 2 ]. Ovaries are made up of three types of cells, and each cell can develop into diverse types of tumors. Approximately 90% of ovarian cancers have been found to be of epithelial origin [ 3 ], including high-grade and low-grade serous carcinoma and clear cell, endometrioid, and mucinous carcinoma, while 7% of OCs have been shown to be stromal types, and OCs from germ cell tumors are found only rarely [ 1 ]. It has been found that there are frequently warning symptoms and signs for OC; however, the earliest symptoms are unclear and hard to detect due to shared gastrointestinal, genitourinary, and gynecological conditions [ 4 ]. A number of barriers to the treatment of the disease exist [ 5 , 6 ]. Despite the early high rates of response to initial chemotherapy and radical surgery for about 70% of patients with relapses and intermediate progression-free 12- to 18-month survival, long-term survival remains poorly understood, with a high risk of reappearance [ 7 ]. Additionally, chemotherapeutic treatments for OC have an undesirable impact on quality of life because of their severe side effects, including fatigue, arthralgia, and neurotoxicity [ 8 , 9 ]. Therefore, understanding the biology of heterogeneous OCs is vital for exploring the disease’s mechanisms more accurately [ 4 ]. Potential therapeutic targets for the management of OC are being explored, such as intrinsic signaling pathways, angiogenesis, hormone receptors, and immunologic factors.

Bevacizumab, the most-studied anti-VEGF-targeted therapy inhibiting angiogenesis in the tumor microenvironment, holds great promise for OC treatment, but redundant angiogenic pathways make the drug show only modest efficacy [ 5 , 6 , 10 , 11 ]. Meanwhile, there has been a surge in clinical trials with several drug candidates that precisely target signal enzymes, which may induce apoptosis and autophagy, targeting the inhibition of angiogenesis in site-specific OC cells [ 12 , 13 , 14 , 15 ]. However, to understand the disease’s pathophysiology, it is essential to thoroughly investigate the regulatory mechanisms in terms of the different molecular layers and time intervals, which may clearly demonstrate the disease dynamics [ 16 , 17 ]. Indeed, the use of molecular profiling for patients with OC may provide effective strategies for treating the disease. Using multi-omics data, it may be possible to gain a comprehensive understanding of the tumor’s biology, which could make it feasible to discover prognostic biomarkers or predictors to facilitate the early diagnosis and prognostic prediction of aggressive and advanced OC, which could ultimately help in treatment decisions [ 4 , 18 , 19 ].

Drug delivery or co-delivery systems represent another crucial approach for OC treatment. Single targeted drugs or multiple targeted agents have been engineered for drug-delivery systems that realize drug release more effectively and reduce toxicity. The present study attempted to evaluate the recent understanding of ovarian cancer associated with signaling mechanisms, targeted therapeutic strategies, and potential drug delivery systems. In particular, the interplay between technological advancement and the management of this heterogeneous disease from diverse perspectives is highlighted.

2. Targeting Numerous Signaling Pathways of Ovarian Cancer

Surgery and chemoradiotherapy are the most frequently used treatment options for ovarian cancer (OC) [ 20 ]. However, severe side effects have been associated with chemo- and radiotherapy (RT), while the only minor therapeutic benefit from RT eventually leads to succumbing to the disease and poor survival outcomes [ 21 ]. Hence, targeting specific signaling pathways would be a promising molecular approach to ovarian cancer therapy in terms of inhibiting tumor growth, cell invasion or migration, and metastasis. It was found that seven major signaling pathways are commonly upregulated in ovarian cancers (> 50%): the PI3K/AKT/mTOR, Jak/STAT, Src, lysophosphatidic acid (LPA), NF-κB, PKCι, and Mullerian inhibitory substance receptor signaling pathways have shown high levels of mutation and/or hyperactivation strongly associated with aggressive phenotypes and advanced disease stages, leading to poor prognosis for the disease [ 4 , 22 ]. In this section, we briefly describe some signaling pathways related to tumorigenesis and metastasis that may be potentially targetable and provide information regarding novel inhibitors currently in clinical trials.

2.1. PI3K/AKT/mTOR Pathway

Phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling is one of the most important pathways controlling cell growth, proliferation, differentiation, and survival [ 23 ]. The pathway is regulated by multiple ligands, such as growth factors (IGF, EGF, TGF, and others), receptor tyrosine kinases (IGF-1R, FGFR, HER2, EGFR, and PDGFR), and various membrane receptors [ 24 , 25 , 26 ]. Indeed, mutations in several components of the pathway are very common in most human cancers, including subtypes of OC [ 27 ]. It has been shown that the aberrant expression and activation of AKT (pAKT) is strongly correlated with poor progression-free and overall survival in epithelial OC [ 28 ]. Whole-genome sequencing analysis revealed that gene breakage frequently inactivates the tumor-suppressive ability of RB1, PTEN, NF1, and RAD51B in high-grade serous ovarian cancer, resulting in acquired chemoresistance [ 29 ]. In particular, OC stemness (CSC), the key regulatory factor of aggressive cancer, is directly modulated by PI3K/PTEN/AKT signaling, causing CSC enrichment, CSC phenotyping maintenance, and multidrug resistance (MDR) [ 30 , 31 ], which leads to abnormal cell proliferation and cancer metastasis through epithelial–mesenchymal transition [ 32 ]. The well-studied mTOR inhibitors for OC include temsirolimus, ridaforolimus, and everolimus, for which phase II clinical trials have been completed [ 13 ]. In recent in vitro and in vivo studies, SPR965, a dual inhibitor of PI3K and mTORC1/2, has been proven to have antitumorigenic activity in diverse solid tumors, including serous ovarian cancer. However, further clinical trials are needed before it can be recommended as a novel targeted therapeutic agent [ 33 ]. Afuresertib, an Akt inhibitor, showed a satisfactory safety profile in platinum-resistant OC in a phase I study, and the drug {"type":"clinical-trial","attrs":{"text":"NCT04374630","term_id":"NCT04374630"}} NCT04374630 is under investigation for use in combined therapy with paclitaxel in platinum-resistant OC in a phase II trial ( Figure 1 ).

PI3K/Akt/mTOR signaling pathway. This pathway is upregulated in ovarian cancer by either (i) receptors of upstream growth factors and ligand stimulation, (ii) indirect activation via cross-talk with JAK/STAT signaling, or (iii) intrinsically via activation of amplified/mutated PI3K or amplification of Akt isoform, or deletion/inactivation in tumor-suppressor protein PTEN. Afuresertib, an Akt inhibitor, is safely used in platinum-resistant ovarian cancer. Most frequently studied mTOR inhibitors in completed OC phase II clinical trials are temsirolimus, ridaforolimus, and everolimus. Ruxolitinib, a JAK inhibitor, is already FDA approved for treatment of polycythemia vera.

2.2. JAK/STAT Signaling Pathway

The JAK/STAT pathway is a crucial signaling pathway that is abnormally activated in OC, and its constitutive activation is strongly related to tumor progression and poor prognosis for the disease [ 34 ]. Hyperstimulation of this pathway has also been found in other cancers, including breast, gastric, lung, prostate, and hematopoietic malignancies [ 35 , 36 , 37 ]. JAK/STAT pathway-mediated tumor progression is mainly due to the expression of a variety of proteins and cytokines involved in cellular proliferation, stemness and self-renewal, survival, and evasion of antitumor immunity [ 37 , 38 ]. Studies have found that more than 50 cytokines and growth factors are responsible for this pathway initiating hematopoiesis, inflammation, and immune suppression in the tumor microenvironment [ 38 ]. STAT is a key driver of immunosuppression through triggering the production of immune checkpoint genes (e.g., PD1, PD-L1, PD-L2, and CTLA-4) [ 39 ], promoting radio- and/or chemoresistance and the failure of targeted immunotherapies [ 22 ].

JAK inhibitors have been found to be essential in the treatment of cancer in recent years. Many JAK inhibitors have demonstrated efficacy in clinical settings, and a number of inhibitors/analogs are currently being studied. Ruxolitinib is a JAK inhibitor already approved by the FDA for the treatment of polycythemia vera; in preclinical studies, it was found that the drug reduced cell viability in OC [ 40 ]. {"type":"clinical-trial","attrs":{"text":"NCT02713386","term_id":"NCT02713386"}} NCT02713386 is being investigated for use in combination therapy with paclitaxel and carboplatin in stage III–IV OC in a completed phase I/II trial [ 13 ]. AZD1480, a small-molecule JAK inhibitor, was demonstrated to suppress OC growth in a mouse model via cascade inhibitory effects on STAT3 phosphorylation, DNA binding, migration, and the adhesion of cultured ovarian cancer cells [ 41 ]. AH057 may effectively block the pathway by inhibiting the function of JAK1/2 kinase, resulting in increased cell cycle arrest and apoptosis, and impaired tumor progression and invasion, as shown in vitro and in vivo [ 42 ]. In CSC, CYT387 administration with paclitaxel was shown to suppress JAK2/STAT3 activity and paclitaxel-induced Oct4 and CD117 (CSC-like marker) expression in a mouse xenograft model, suggesting the development of CSC-targeted therapy [ 43 ]. Higher levels of aldehyde dehydrogenase (ALDH), a characteristic feature of endometrial cancer progenitor and stem cells, upregulates IL-6 and signal transducer CD126 and GP130 expression, while the blockade of the IL6 receptor dramatically suppresses downstream effector IL6/JAK1/STAT3 signaling, eventually reducing tumor cell growth [ 44 ]. Taking all the data together, the continuous activation of the JAK/STAT pathway is certainly implicated in many types of human malignancies, while the potential effect of JAK inhibitors on cancer development remains a source of concern [ 45 ]. Therefore, the safety and benefits of JAK inhibitors still need to be determined.

2.3. Wnt/β-Catenin Pathway

The interest in Wnt signaling began in 1982 and has steadily increased due to the extreme renewal, proliferation, and differentiation properties of CSCs, thus showing an important role for them in tumorigenesis and therapy resistance in many malignancies [ 46 ]. Wnt signaling exemplifies several pathways, such as Notch–Delta, Sonic–Hedgehog, Hippo, and transforming growth factor β (TGF-β)/bone morphogenetic protein (BMP), which are directly implicated in developmental and evolutionary processes [ 47 ], thereby facilitating its widespread activity. Wnt signaling seems to regulate tumorigenesis in ways that are both β-catenin-dependent (canonical, primarily for cell proliferation) and β-catenin-independent (noncanonical, controlling cell polarity and movement) [ 48 ]. Although Wnt signaling has been linked to the incidence and progression of ovarian cancer [ 49 ], its possible consequences in ovarian cancer are still being investigated.

Mutations in the components of the Wnt pathway are causal factors for multiple growth-associated pathologies in cancer [ 47 ]. A number of possible mechanisms are involved in Wnt pathway hyperactivation, including the upregulation of ligands and receptors, the downregulation of the Wnt/beta-catenin pathway inhibitors, and altered protein function, which in turn control the interaction between beta-catenin and E-cadherin or beta-catenin and TCF. These abnormalities have been noted in EOC, especially in the high-grade serous subtype [ 50 ]. Furthermore, the involvement of several noncoding RNAs (IncRNAs, miRNAs, and circRNAs) in regulating beta-catenin signaling in EOC has recently been demonstrated [ 51 ]. Wnt signals regulate the cell cycle at several points. In endometrial and mucinous subtypes of EOC, mutations have been observed in, for example, the CTNNB1, AXIN, and APC genes [ 50 ]. The crucial role of the Wnt pathway in OC development, progression, angiogenesis, metastasis, and chemoresistance is supported by its strong CSC (cancer stem cell) self-renewal, EMT (epithelial–mesenchymal transition), and invasion capabilities and tumor immunity suppression [ 52 ]. Apart from tumorigenesis, there is a direct impact of the Wnt signaling pathway on immune responses. Recently, several cancer-specific inhibitors of this signaling pathway have been identified, including WNT974, which increases antitumor immunity in ovarian cancer [ 53 ]. Thus, β-catenin may be a promising therapeutic target in chemoresistance subtypes of EOC with CSCs.

2.4. Apoptotic Signaling Pathway’

Apoptosis is a characteristic and orderly energy-mediated biochemical cellular suicide process that maintains homeostatic equilibrium between the proportion of cell death and cell formation in multicellular creatures [ 54 , 55 ]. It is well evidenced that apoptosis induction acts as a hallmark barricade to cancer development [ 56 , 57 , 58 ]. The B-cell lymphoma-2 (BCL-2) family and inhibitors of apoptotic proteins (IAPs) are the predominant components of intrinsic apoptotic pathway induction through caspase activation, which regulates mitochondrial membrane permeabilization through apoptotic switching [ 59 ]. Alternatively, the extrinsic apoptotic pathway triggers tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) to the cell surface receptor signaling cascade [ 60 ]. Several studies imply that both signaling cascades may be activated simultaneously to induce apoptosis in human ovarian cancer [ 61 , 62 ]. In particular, it has been proposed that apoptosis induction is broadly mediated by caspase-3 pathway activation, which has been established by increased sensitivity to paclitaxel using adenoviral type 5 E1A in human HER-2/neu-overexpressing ovarian cancer SKOV3.ip1 cells. In this pathway, caspase-3 executes the proteolytic cleavage of cellular proteins to progress apoptosis [ 63 ].

Enzastaurin ( {"type":"entrez-nucleotide","attrs":{"text":"LY317615","term_id":"1257423630","term_text":"LY317615"}} LY317615 .HCl), a radiosensitizing, ATP-competitive, discriminating protein kinase C beta (PKC-beta) inhibitor, is an alternative drug that inhibits tumor cell growth through the upregulation of caspase-3 and caspase-9′s proapoptotic activity [ 62 ]. Among different analyses, a combination treatment with enzastaurin and pemetrexed was shown to cause apoptosis induction in chemotherapy-resistant ovarian cancer HEY cells, controlling phosphorylated GSK3β and inhibiting mitogen-activated protein kinase ERK-1/2 (extracellular signal-regulated kinase)-mediated cell growth [ 64 ]. In addition, a current study reveals that metformin induces an apoptotic pathway in OVCAR-3 and OVCAR-4 cell lines in an AMP-activated protein kinase (AMPK)-independent manner, resulting in S- and G2/M-phase cell cycle arrest. Metformin may also induce apoptosis by downregulating Bcl-2 and Bcl-xL protein expression and caspase 3/7 activation, and augmenting Bax and Bad expression in human OVCAR-3 and OVCAR-4 cell lines. Furthermore, metformin-induced apoptosis is augmented by the addition of cisplatin without modulating the appearance of Bcl-2 proteins in the OVCAR-3 cell line, although BcL-2 was expressed in the OVCAR-4 cell line [ 65 ].

Resveratrol, a small polyphenol compound, increases apoptosis induction by activating it in an AMPK-dependent manner, and activates caspase 3, which leads to the inhibited expression and activation of mTOR, a downstream signaling target of AMPK, in ovarian cancer cells [ 66 ]. Moreover, TRAIL has been reported as an alternative therapeutic target for ovarian cancer management, although the targeted restriction of tyrosine kinase family proteins (PYK2 and FAK) and BCL-XL works synergistically and increases apoptosis in human ovarian carcinoma cell lines. The study revealed that the mitochondrial division inhibitor-1 (mdivi-1) increases the sensitivity of ovarian cancer cells to cell surface ligands such as FAS, TRAIL, and TNF-alpha [ 67 ]. A recent study demonstrated that berberine (BBR), a potent anticancer drug, combined with cisplatin (DDP) enhanced apoptosis by inhibiting PCNA and Ki67 expression and upregulating caspase-3, caspase-8, RIPK3, and MLKL expression and activation in the OVCAR-3 and POCCL ovarian cancer cell lines [ 68 ] ( Figure 2 ).

Apoptosis signaling in cancer cells. Metformin-induced apoptotic pathway in ovarian cancer cell lines stimulates AMP-activated protein kinase (AMPK)-independent apoptotic pathway. Berberine activates caspase-8 and caspase-3-mediated apoptotic pathway. Mdivi-1 stimulates TRAIL-induced extrinsic pathway.

3. Autophagy Modulation in Ovarian Cancer Management

Autophagy is a self-digestion process that assists in maintaining cellular homeostasis by recycling unwanted or damaged toxic cellular organelles in cells [ 69 , 70 ]. The modulation of autophagy has been implicated in regulating several cancers [ 71 , 72 ]. It has been suggested that autophagy is an important function in ovarian cancer via the expression of autophagy-related proteins, which comprise the microtubule-associated proteins light chain (LC-3), beclin-1, and p53 [ 12 ]. Beclin-1 is a tumor-suppressor protein that has an essential checkpoint role in apoptosis and autophagy in tumor cells [ 73 ]. Beclin-1 expression has been found to be downregulated in ovarian cancers compared to benign lesions [ 74 ], suggesting the predictive potential of the beclin-1 protein in OC. Furthermore, the cytoplasmic localization of p53 mutants has been shown to prevent autophagy [ 75 ]. Additionally, Bcl-2 expression was found to prevent autophagy by interacting with beclin-1, and the overexpression of mutant p53 protein may impact autophagy in ovarian cancer cells [ 76 ]. Later, the p53-mediated regulation of autophagy was validated in a clinical study [ 77 ].

Aplasia Ras homolog member I (ARH1), another protein, has been found to be upregulated in autophagy via the mTOR-dependent pathway, which activates autophagy-mediated dormancy [ 78 ]. In approximately 70% of cases of ovarian cancer, PI3K/AKT/mTOR pathways have been shown to be constitutively triggered by autophagy, which has been considered to be a therapeutic target of ovarian cancer [ 79 ]. It was reported that a specific PI3K inhibitor, LY294002, given as treatment for ovarian cancer in an established mouse model, prevented ovarian cancer cell proliferation [ 80 ]. Additionally, the cellular cytotoxic effects of novel chemotherapeutic agents were shown to be efficiently improved through cotreatment with a noncompetitive AKT inhibitor, TAS-117, in in vivo models of ovarian cancer [ 81 ]. Sirtuin 3 (Sirt3), a member of the sirtuin protein family, performs an essential function in maintaining ovarian cancer intracellular homeostasis in a close mutual monitoring relationship, as well as autophagy. Studies showed that metformin-mediated Sirt3 overexpression encouraged mitochondrial dysfunction and apoptosis via the activation of AMPK in ovarian cancer cells [ 82 ]. In addition, Sirt3 may similarly control autophagy through glutathione S-transferase and JNK-mediated autophagy pathways, and Sirt3 knockdown was shown to relieve S1-induced apoptosis in ovarian cancer cells [ 83 ] ( Figure 3 ).

Modulation of autophagy signaling in relation to Sirt3 and autophagy in ovarian cancer. Metformin-mediated Sirt3 overexpression triggers AMPK, which increases activation of LC3. Sirt3 is also involved in autophagy regulation through MAPK/JNK/mTOR autophagy pathway. Several autophagy-related genes, such as beclin-1, p62, LKB1, and VPS34 complex, stimulate autophagy initiation. Sirt3 also activates FOXO3a, which subsequently activates p62 and autophagy. Transcription factor p53 activates and promotes synthesis of autophagy proteins, and high cytoplasmic levels of p53 may result in inhibition of autophagosome formation.

4. Novel Treatment Strategies for Epithelial Ovarian Cancer (EOC)

The identification of novel therapeutic targets has been linked to better prognosis in ovarian cancer (OC). Advancements in the understanding of ovarian cancer biology have resulted in the development of numerous molecular targets, including growth factor receptors, cell cycle regulators, signal transduction pathways, and angiogenic mechanisms. The molecularly targeted agents possess higher selectivity and lower toxicity than conventional chemotherapy [ 84 ]. Major therapeutic targets used alone or in combination with cytotoxic drugs for OC treatment and new drugs in clinical trials are reviewed in this section.

4.1. Therapeutic Approaches and Targets in Ovarian Cancer

Given the enormous number of potential epithelial ovarian cancer treatments, it is useful to review the pathobiology of the disease to find relevant targets. The drug targets telomerase, HER2, AKT EGF-R, VEGF-R, and p53 are currently being studied in clinical trials [ 13 , 85 ]. Some specific targets are found only in OC, while some found in a wide variety of cancers [ 85 , 86 ] are briefly discussed.

4.2. Angiogenesis and VEGF Signaling Pathway

Angiogenesis is the process of forming new blood vessels, which enables nutrients and oxygen to enter the surrounding tissues, thus promoting tumor cell proliferation, invasion, and metastasis [ 87 , 88 ]. The growth of blood vessels or new capillaries starts with vasodilation, increased vascular permeability, stromal disintegration, and endothelial cell proliferation and migration [ 89 , 90 ]. Researchers have discovered that receptor tyrosine kinases (RTKs), VEGF and its receptor (VEGFR), and Flk-1/KDR RTK play key roles in pathological angiogenesis, particularly tumor neovascularization [ 91 ]. An immediate impact on tumor growth is observed (slowdown or stoppage) when the VEGF signaling pathway is blocked or inhibited [ 92 ]. This insight into the mechanism of angiogenesis led to the establishment of several treatment methods targeting the VEGF pathway.

Bevacizumab is an anti-VEGF antibody and the most studied VEGF-targeting therapy for ovarian cancer [ 93 , 94 ]. The best response of the drug has been found in recurrent ovarian cancer, and it can be administered alone or with chemotherapy [ 95 , 96 , 97 ]. Current ovarian cancer clinical trials with bevacizumab show promising results (PFS) in two major first-line studies, ICON7 [ 98 ] and GOG 218 [ 99 ]. Along with carboplatin/paclitaxel, the GOG study uses bevacizumab as part of a triplet to treat patients with minimal cytoreduction of ovarian cancer [ 100 ]. Other potential VEGF-targeting medicines, including soluble decoy VEGF receptors such as aflibercept (VEGF TRAP) [ 101 ] and VEGF kinase inhibitors such sunitinib (SU11248, Sutent, Pfizer), have shown significant treatment benefit in EOC patients [ 14 ].

4.3. ErbB Family Kinases

The EGF family of RTKs, also known as ErbB or HER receptors, has been widely investigated in pharmacological research targeting human cancer. Numerous hypotheses have been suggested for HER2-mediated cell transformation through multiple mechanisms, such as EGFR and ErbB-3 interaction, which exhibit tyrosine phosphorylation and the activation of a cytoplasmic signaling pathway, while ErbB1 and ErbB2 homodimers transform fibroblasts using differential signaling [ 102 , 103 ]. Trastuzumab (Herceptin), a targeted monoclonal antibody for ErbB2, is approved for treating ErbB2 1 breast cancer. According to the GOC study, trastuzumab had limited action in ovarian cancer [ 104 ]. A partial but long-lasting response was observed when combination therapy with trastuzumab–pertuzumab was used in a young woman with high-grade serous ovarian cancer (FIGO stage IV) [ 15 ]. Furthermore, a number of EGF-R targeting agents are currently in clinical trials [ 105 , 106 , 107 ], while some agents have shown exciting antitumor performance in CRC-based xenograft models and cell lines, such as cabozantinib, and are awaiting clinical trials [ 10 ]. Other receptor-binding inhibitors, such as cetuximab, work differently from the TKIs gefitinib and erlotinib. However, erlotinib and gefitinib alone show poor response rates (5–10%) in EOC [ 11 , 108 ] owing to PI3K-pathway-mediated tumor resistance through p38 MAPK activation and the following DNA repair [ 109 ]. Thus, targeting of EGFR, along with inhibition of p38 MAPK or DNA repair, may improve the efficacy of EGFR mediated treatment in ovarian cancer.

4.4. Ansamycins and HSP90 Degradation

Benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin (17-AAG) is an early described tyrosine kinase inhibitor that interacts with HSP90, leading to the proteasomal degradation of Hsp90-targeted proteins [ 110 , 111 ]. Many biological functions of 17-AAG are common with those of its parent compound geldanamycin (GA), including the ability to inhibit the growth of tumor cells [ 112 ]. It has been shown that Hsp90 originating from tumor cells has a 100-fold higher affinity to bind with 17-AAG than Hsp90 from normal cells, and also a strong affinity for oncogenic signaling proteins such as HER-2/ErbB2, Akt, Raf-1, mutated p53, and Bcr-Abl, emphasizing it as an attractive candidate for new treatment options in OC. For example, ErbB2 appears to be a potential target, because high ErbB2-expressing cells are more susceptible to ansamycin-induced growth inhibition at minimal doses. Surprisingly, this effect seems to be linked to ErbB3- and PI3K/AKT-dependent pathways [ 113 ]. Ansamycins are known to have a strong affinity for the AKT protein. For AKT to remain stable, HSP90 needs to be linked to it, and the addition of HSP90 inhibitors results in a gradual decrease in AKT function [ 114 , 115 ]. Thus, the PI3K–AKT signaling pathway is highly active in the progression of OC, and combination therapy of 17-AAG with cisplatin or taxol may enhance cell apoptosis via the inhibition of PI3K/Akt signaling. In addition, the combination of olaparib and 17-AAG may increase drug sensitivity in HR-proficient EOC and reverse multidrug resistance [ 116 ], suggesting the rational use of 17-AAG in ovarian cancer.

4.5. 26S Proteosome Inhibition with PS341 (Bortezomib)

The activity of the proteasome directly represents a promising therapeutic strategy for cancer. PS341 (bortezomib), a dipeptide boronic acid derivative, prevents protein degradation by the reversible inhibition of the 20S proteasome. Cyclins (CDKs) and IkB proteins, which are corepressors of nuclear factor-kappa B (NF-κB) activation, seem to be the prospective targets. The inhibition of IkB degradation reduces NF-κB transcription factor activity [ 117 ]. Although NF-kB appears to have a strong antiapoptotic function, the use of PS-341 and NF-κB blockers tends to increase chemotherapy-induced apoptosis.

4.6. Tubulin-Targeting Molecules

Anticancer drugs, including taxanes and vinca alkaloids, which are directed against microtubules, have long been used as first-line drugs for breast cancer and a wide range of other cancers, including ovarian, prostate, head and neck, and lung cancers [ 86 ]. Polyglutamated paclitaxel (CT2103), a cytotoxic agent, was found to have fewer side effects and better treatment responses than paclitaxel in phase III clinical trials [ 118 ]. Compared to the original paclitaxel, this new formulation has a decreased risk of hypersensitive side effects and can be administered more quickly. Indeed, it shows taxane-like efficacy in recurrent OC, with a response rate of 23% in individuals who have received limited prior therapy; however, oral treatment results in low bioavailability [ 119 ].

4.7. Ovarian Cancer-Specific Targets: MUC16/CA125

For more than two decades since its discovery, CA125 antigen has been permitted for clinical use for the OC screening of high-risk women in the US. Later, it was suggested as a predictive marker in preinvasive OC [ 120 ]. Although it has limited sensitivity and specificity, the CA125 antigen is strongly related to epithelial OC. The diagnostic performance of this biomarker has been useful in primary care, especially in women ≥ 50 years old [ 121 ]. Lloyd and colleagues identified the gene that encodes the CA125 antigen, which was subsequently called MUC16 [ 122 ]. The affinity for the binding of CA125 antigen with the murine monoclonal antibody Mab-B3.13 (also known as OvaRex) is strong. Thus, CA125-targeted murine antibodies have been employed as potential therapeutic agents. In a phase I/II clinical trial, patients with recurrent OC developed immunity, such as antibodies and T cells, to oregovomab and CA125 given as third-line therapy, and anti-idiotype antibodies were found in 66% of patients [ 123 , 124 ]. This suggests that vaccination using specific anti-idiotypic antibodies could ameliorate the survival benefit for patients with few side effects in recurrent OC. Therefore, the application of the noninvasive immunotherapy in combination chemotherapy may be a potential therapeutic strategy for improved survival in OC [ 125 ].

5. Drug-Delivery System for Ovarian Cancer Treatment

Treating OC using traditional chemotherapy has serious limitations, including the rapid clearance of drugs, undesirable biodistribution, and adverse side effects. To minimize these limitations, researchers have focused on a variety of drug delivery systems (DDSs) with which to encapsulate anticancer agents so they can directly reach tumor cells. Many types of DDSs have been developed, such as liposomes, drug conjugates, microspheres, micelles, nanoparticles, implants, and injection depots [ 126 ]. The benefits of using a DDS over conventional chemotherapy include the lower nonspecific toxicity, increased exposure of cancer cells to the drugs, circumvention of drug resistance, and improved drug solubility.

In 1996, researchers published the first report on biodegradable and biocompatible nanoparticle compositions using poly(lactic-co-glycolic) acid. Various improvements and adjustments have been made to the material, and nanoparticle synthesis processes have been continually updated. Recently, there has been growing interest in employing naturally existing protein cages, such as viral particles, as drug carriers [ 127 , 128 , 129 ], while the majority of research has focused on designing nanoparticles for delivering chemotherapeutic agents such as cisplatin, doxorubicin, and paclitaxel as an advanced therapeutic option for OC [ 130 ]. The polymers most widely used in drug delivery systems include polylactic acid (PLA), polylactic-co-glycolic acid (PLGA), poly(γ-glutamylglutamine), polyethylene oxide, modified poly -ε-caprolactone (PCL), and polypropylenimine (PPI) [ 130 , 131 , 132 ]. In addition to designing diverse nanoparticle materials, it is possible to make various surface modifications to either sustain the controlled release of drugs or enhance drug stability [ 133 ].

5.1. Single-Agent Delivery Systems

To enhance the efficacy of cancer treatment, a minimum of one chemotherapeutic agent is encapsulated or embedded into nanoparticles. The drug cisplatin is widely used as first-line therapy for ovarian cancer, but it has a dose restriction due to its nephrotoxicity [ 134 ]. Therefore, researchers have made efforts to improve the distribution of cisplatin and reduce kidney damage by using surface modification and nanoparticle engineering techniques [ 135 , 136 ]. Polyisobutylene-maleic acid (PIMA) linked to glucosamine (GA) was used to generate cisplatin nanoparticles by forming platinum (Pt) complexes toward each monomeric unit at various polymer-to-Pt ratios [ 135 ].

The chemotherapeutic agent paclitaxel is widely used in combination with a therapeutic drug carrier, but the small molecule is hydrophobic in nature (DrugBank, DB01229). To overcome the obstacle of its low aqueous solubility, the clinical dosage is used with absolute ethanol, making a combination called Cremophor EL, which is physiologically and pharmacologically potent; however, it has been shown to cause severe acute hypersensitivity [ 137 ]. ABI-007 (Abraxane ® ), an alternative to Cremophor EL, was later developed to improve the solubility of paclitaxel [ 138 ], and an albumin-bound paclitaxel nanomaterial was approved by the FDA for treating different types of cancers [ 139 ]. It is now a feasible alternative to paclitaxel in Cremophor EL drug formulations. Feng et al. developed nanoparticles comprising paclitaxel joined to PGG via an ester bond [ 140 ].

In addition to breast cancer treatment, the chemotherapeutic drug doxorubicin (Dox) is also extensively used in ovarian cancer, but it presents serious cardiotoxicity. To lessen its toxicity, doxorubicin could be encapsulated and delivered via a drug delivery system. Zeng et al. developed a naturally occurring biological scaffold for synthesizing doxorubicin-releasing nanoparticles by infecting the cucumber mosaic virus (CMV) [ 141 ].

5.2. Co-Delivery Nanoparticles

To achieve superior efficacy, particularly in chemotherapy, and minimize the toxicity of single-drug therapy, nanodrug co-delivery systems (NDCDSs) have been developed, using combinations of at least two anticancer drugs with different physicochemical and pharmacological properties [ 142 ]. It is possible to incorporate drugs, antibodies, and siRNA into the nanoparticles, facilitating the administration of numerous drugs in a single dose. For example, paclitaxel and ceramide were co-delivered utilizing PEO-PCL nanoparticles [ 143 , 144 ]. Ceramide buildup within cancer cells induces apoptosis and enhances the effectiveness of chemotherapy. However, ceramide cannot be administered to the systemic circulation due to its hydrophobicity, limited cell permeability, and metabolic inactivity. Therefore, biocompatible and biodegradable nanoparticles with paclitaxel and ceramide co-delivery were developed for effective ovarian cancer treatment.

There have also been significant developments in siRNA-based drug co-delivery systems. By using polypropylenimine (PPI), a new dendrimer that efficiently transported paclitaxel and a siRNA specific for the CD44 mRNA was synthesized [ 145 , 146 , 147 ]. CD44, a glycoprotein present on the membranes of cancer cells, plays an essential role in cancer development and progression. It was expected that the siRNA-mediated inhibition of the cell surface CD44 marker would prevent the development of metastasis and improve the efficacy of chemotherapy treatment. A delivery vehicle was developed to overcome the slow penetration of siRNA into the cell membrane. A polypropylenimine (PPI) dendrimer was designed along with the chemotherapeutic drug paclitaxel to deliver siRNA for CD44 suppression. [ 146 ]. However, the issues of biodegradation, bioavailability, instability, tissue distribution, and possible toxicity raise concerns about their safety for long-term administration [ 148 ]

6. Limitations and Chemoresistance of Ovarian Cancer Therapy

More than half (58%) of OC patients are diagnosed at an advanced stage (III or IV), which prevents early diagnosis and leads to poor prognosis [ 149 ]. The standard of care for advanced OC includes cytoreductive tumor surgery followed by chemotherapy and/or radiotherapy regardless of tumor heterogeneity, hormone therapy, etc. [ 150 ]. However, chemotherapy resistance is still considered a major challenge when attempting to cure patients and achieve a favorable prognosis because the exact treatment choice depends on a number of factors, including the cancer molecular subtype, stemness, and clinical stage; the disease dynamics; and the person’s age and overall health [ 151 ].

A variety of chemotherapeutic agents for treating ovarian cancer that can be used singly or in combination are available [ 13 , 152 ]. The most commonly used chemotherapeutic agents are platinum-based drugs (cisplatin and carboplatin) and taxane family drugs (paclitaxel and docetaxel) [ 153 ]. Unfortunately, these agents are associated with different types of life-threatening side effects, including sustained nausea and vomiting, hair loss, mouth sores, acute renal injury, ototoxicity, infertility, anemia, leukopenia, thrombocytopenia, and long-term peripheral neuropathy [ 9 ]. In fact, chemotherapeutic agents have poor bioavailability, high dose requirements, low therapeutic indices, and nonspecific targeting, which ultimately lead to elevated toxicity in normal cells and drug resistance in cancer cells [ 148 ].

Chemotherapy resistance is a complex phenomenon in which cancer cells evade the effects of chemotherapeutics. Multidrug resistance (MDR) is considered the main cause of chemotherapy treatment failure and low patient survival rates [ 154 ]. With MDR, cancer cells become insensitive to both cytostatic drugs and pharmaceutical agents. The resistance emerges rapidly through multiple mechanisms such as drug inactivation, alterations in the drug target, drug efflux (e.g., P-glycoprotein), DNA damage repair, the evasion of apoptosis [ 154 ], the activation of drug-metabolizing enzymes (e.g., cytochrome P450 and glutathione S-transferase) [ 155 ], and genetic (gene mutation and amplification) and epigenetic (methylation and acetylation) changes [ 154 ]. Among these mechanisms, some favor drug resistance by reducing the effective concentrations, while others contribute by inhibiting the toxic action of the drugs [ 156 ]. However, due to advancements in DNA microarrays, proteomics technology, and the development of novel targeted therapeutics, new strategies for overcoming drug resistance can be provided.

Radiotherapy has been used extensively for the treatment of dysgerminomas and the clearance of residual malignancy after surgical removal. However, despite the therapeutic effects with regard to the clinical management of ovarian cancer, the development of resistance is apparently unavoidable, which impedes further treatment [ 157 ]. Therefore, understanding the underlying molecular mechanism of therapeutic resistance is crucial in the management of ovarian cancer and drug discovery, which will improve clinical outcomes.

7. Technological Advances in Identifying Novel Biomarkers of Ovarian Cancer

Despite the widespread use of traditional and modern technology for the detection and prognosis of OC, it remains the deadliest gynecological malignancy in terms of early diagnosis and management [ 150 ]. Therefore, it is urgent to search for novel diagnostic and prognostic biomarkers of ovarian cancer in order to understand the disease’s biology, which could provide guidance for improved treatment decisions. Currently, multi-omics approaches (genomics, transcriptomics, proteomics, and metabolomics) provide unprecedented opportunities to understand disease pathophysiology at different molecular layers, which can facilitate the accurate prediction of disease biology. The molecular markers identified by these approaches are crucial for disease prognosis by predicting tumorigenesis, progression, and metastasis, based on the continuous improvement of the technologies [ 16 , 17 , 158 , 159 , 160 ]. The discovery of novel biomarkers could guide targeted therapeutic decisions by accurate prognostication, thereby minimizing unwanted side effects and therapy resistance, which could improve the management of ovarian cancer toward achieving a better quality of life and patient survival outcomes ( Table 1 ) [ 161 , 162 , 163 ].

Emerging prognostic biomarkers in ovarian cancer and novel technologies.

In genomics, oncogenes, tumor-suppressor genes, and epigenetic modifications of DNA can be detected at the DNA level through gene mutation and DNA methylation microarrays, genome-wide association studies, and sequencing [ 163 , 167 , 175 ]. The mutation of TP53 is the most frequent genetic abnormality; it causes loss of function in OC and is demonstrated in 60–80% of patients in both sporadic and familial cases [ 4 ]. DNA repair defects were found in 10–15% of ovarian cancers; the lifetime risk for BRCA1 is about 30–60% and that for BRCA2 is 15–30% in those who have a genetic defect promoting the development of OC [ 4 ]. In addition, the epi-biomarkers RUNX3/CAMK2N1, ARNTL, and Fkbp1/Pax9, detected by GWA, CpG island microarrays, ChIP-PCR, and Sanger sequencing, can predict prognosis, clinical outcomes, and chemotherapy resistance [ 161 , 162 , 167 ].

In transcriptomics, coding mRNA and ncRNA microarrays and RT-qPCR are widely used to explore disease biology and dynamics with a comprehensive assessment of changes in expression patterns by observing the differential expression of genes and differently spliced transcripts at the RNA level, including mRNA, miRNAs, lncRNAs, and circRNAs in ovarian cancer ( Table 1 ). In some cases, high collagen type XI alpha 1 (COL11A1) expression at the mRNA level is associated with advanced disease stage, recurrence, and poor survival via the TGF-β1–MMP3 axis and pathways [ 170 ]. The forkhead box M1 (FOXM1) oncogene is upregulated (mRNA) in EOC; it is involved in cell cycle progression predominantly through the regulation of cell-cycle-checkpoint genes and is a potential prognostic biomarker for chemoresistant OC [ 163 ]. The circCELSR1, a circular RNA (circRNA), was found to be dramatically upregulated in PTX-resistant OC, as determined by microarray analysis and quantitative real-time PCR, dual-luciferase reporter assays, and RNA immunoprecipitation, and the circCELSR1–miR-1252–FOXR2 axis was finally established as a novel therapeutic target in OC [ 158 ].

Regarding protein levels, differentially expressed proteins, antibodies, cytokines, growth factors (proliferating and proangiogenic factors), etc., could be very useful in the early diagnosis and prognosis of OC through high-throughput techniques such as LC-MS, ITRAQ tagging coupled with mass spectrometry, reverse-phase protein arrays, etc. [ 16 , 19 , 172 , 173 ]. For example, serotransferrin, AA1, Hpx, CRP, and albumin, found to be differentially expressed in OC, can be used in a multimarker test for the screening and detection of ovarian cancer [ 16 ]. Retinol-binding protein 4 (RBP4) is an adipocyte-derived cytokine that contributes to the pathogenesis of endometriosis by increasing the viability, proliferation, and invasion of endometrial stromal cells [ 172 ]. Therefore, novel efficient diagnostic platforms are needed to detect OC biomarkers with high sensitivity and selectivity, miniaturization, versatility, and high throughput. The identification of new biomarkers for early diagnosis is also required in order to increase the survival rate and quality of life of ovarian cancer patients.

8. Conclusions

Ovarian cancer is a deadly gynecological illness that affects women worldwide. Due to a lack of precise diagnostic biomarkers, the majority of women with ovarian cancer are diagnosed at an advanced stage, which reduces their chances of survival. Chemotherapy resistance in late-stage ovarian cancer is a significant clinical challenge, because various signaling pathways are involved in the pathophysiology of chemotherapy resistance. In order to address this, the focus is on developing biomarkers and diagnostic tools that can help with the early detection and prediction of the disease. It is hard to determine the molecular changes occurring in ovarian cancer, which is very important for choosing the right therapeutic drugs, the success of which can improve clinical outcomes. Thus, it is critical to understand the biology of this heterogeneous disease in order to conduct more precise investigations into its mechanisms. Advancements in our understanding of ovarian cancer biology has resulted in the identification of a variety of molecular targets, including signal transduction pathways, growth factor receptors, angiogenic processes, and cell cycle regulators, as well as drug delivery systems. In addition, advances in therapeutic technology have allowed significant insight into the molecular complexity, creating opportunities for diagnosis and prognosis to inform new therapeutic efforts which have the potential to significantly improve the overall survival rate and quality of life of patients with ovarian cancer.

Author Contributions

S.A. and M.A.R. were substantially involved in the conception and design of the work. M.N.H. (Mohammad Nazmul Hasan), H.A., M.A.R., P.N., R.I., Y.S., M.S.G., M.N.H. (Md Nazmul Huda), J.C. and S.H. prepared the original draft. M.H.R., H.A. and S.A. provided the figures and table. S.S.K., T.G.C., N.M.N., J.H., B.K., I.K., W.C. and S.A. reviewed and edited the manuscript. All authors have read and agreed to the published version of the manuscriptt.

This work was supported by National Research Foundation of Korea (NRF) grants funded by the Korean government (MEST) (NRF-2020R1I1A1A01069013 to TGC, and NRF-2018R1A6A1A03025124 and NRF-2020H1D3A1A04080389 to SSK).

Institutional Review Board Statement

Informed consent statement, data availability statement, conflicts of interest.

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Ovarian Cancer

• What Is Ovarian Cancer?
• Key Statistics for Ovarian Cancer

What's New in Ovarian Cancer Research?

• Ovarian Cancer Risk Factors
• What Causes Ovarian Cancer?
• Can Ovarian Cancer Be Prevented?
• Can Ovarian Cancer Be Found Early?
• Signs and Symptoms of Ovarian Cancer
• Tests for Ovarian Cancer
• Ovarian Cancer Stages
• Survival Rates for Ovarian Cancer
• What Should You Ask Your Doctor About Ovarian Cancer?
• Surgery for Ovarian Cancer
• Radiation Therapy for Ovarian Cancer
• Chemotherapy for Ovarian Cancer
• Hormone Therapy for Ovarian Cancer
• Targeted Drug Therapy for Ovarian Cancer
• Immunotherapy for Ovarian Cancer
• Treatment of Invasive Epithelial Ovarian Cancers, by Stage
• Treatment for Epithelial Tumors of Low Malignant Potential
• Treatment for Germ Cell Tumors of the Ovary
• Treatment for Stromal Tumors of the Ovary, by Stage
• Living as an Ovarian Cancer Survivor
• Second Cancers After Ovarian Cancer
• If You Have Ovarian Cancer

Risk factors and causes

Early detection.

Scientists continue to study the genes responsible for familial ovarian cancer. This research is beginning to yield clues about how these genes normally work and how disrupting their action can lead to cancer. This information eventually is expected to lead to new drugs for preventing and treating familial ovarian cancer.

Research in this area has already led to better ways to detect high-risk genes and assess a woman's ovarian cancer risk. A better understanding of how genetic and hormonal factors (such as oral contraceptive use) interact may also lead to better ways to prevent ovarian cancer.

New information about how much BRCA1 and BRCA2 gene mutations increase ovarian cancer risk is helping women make practical decisions about prevention. For example, mathematical models have been developed that help estimate how many years of life an average woman with a BRCA mutation might gain by having both ovaries and fallopian tubes removed to prevent a cancer from developing. Studies have shown that fallopian tube cancers develop in women with BRCA gene mutations more often than doctors had previously suspected. However, it is important to remember that although doctors can predict the average outcome of a group of many women, it is still impossible to accurately predict the outcome for any individual woman.

Studies suggest that many primary peritoneal cancers and some ovarian cancers (such as high-grade serous carcinomas) actually start in the fallopian tubes. According to this theory, the early changes of these cancers can start in the fallopian tubes. Cells from these very early fallopian tube cancers can become detached and then stick to the surface of the peritoneum or the ovaries. For reasons that are still not understood, these cancer cells may grow more rapidly in their new locations.

This theory has important implications for preventing ovarian cancer because having the ovaries removed early can cause problems from lack of estrogen, such as bone loss, cardiovascular disease, and menopause symptoms. Some experts have suggested recently that some women who are concerned about their ovarian cancer risk (especially those with a strong family history and/or BRCA gene mutations) consider having just their fallopian tubes removed first. They then can have their ovaries removed when they are older. This approach lets women keep their ovaries functioning for longer, but because of that, it might not help breast cancer risk as much. This is an active area of research.

Other studies are testing new drugs for ovarian cancer risk reduction.

Researchers are constantly looking for clues such as lifestyle, diet, and medicines that may alter the risk of ovarian cancer.

Being able to find ovarian cancer early could have a great impact on the cure rate. Researchers are testing new ways to screen women for ovarian cancer. One method being tested is looking at the pattern of proteins in the blood (called proteomics ) to find ovarian cancer early.

The use of new imaging techniques such as Functional MRI are being evaluated in ovarian cancers. PET/CT scans are also being studied to see where they may be best used for ovarian cancer.

For women who have an ovarian tumor, a test called OVA1 can measure the levels of 5 proteins in the blood. The levels of these proteins, when looked at together, are used to determine whether a woman's tumor should be considered low risk or high risk. If the tumor is labeled "low risk" based on this test, the woman is not likely to have cancer. If the tumor is considered "high risk," the woman is more likely to have a cancer, and should see a specialist (a gynecologic oncologist). This test is NOT a screening test and it is NOT a test to decide if you should have surgery or not. It is meant for women who have an ovarian tumor where surgery has been decided but have not yet been referred to a gynecologic oncologist.

Treatment research includes testing the value of currently available methods as well as developing new approaches to treatment.

Chemotherapy

New chemotherapy (chemo) drugs and drug combinations are being tested.

When the drugs cisplatin and carboplatin stop working, the cancer is said to be platinum resistant . Studies are looking for many ways to make these cancers sensitive to these drugs again. Different strategies include:

• Looking closely at what specific mechanisms and proteins are involved in the making ovarian cancer cells resistant.
• Developing drugs that can keep the cancer cells from becoming resistant to the chemo by blocking channels that pump chemotherapy out of the cancer cell.
• Trying to determine the details of certain cancer cells where the DNA is not damaged by chemotherapy which allows it to keep growing.

Although carboplatin is preferred over cisplatin in treating ovarian cancer if the drug is to be given IV, cisplatin is used in intraperitoneal (IP) chemotherapy. Studies are looking at giving carboplatin for IP chemo.

Another approach is to give IP chemo during surgery using heated drugs. This, known as heated intraperitoneal chemotherapy or HIPEC, can be effective. More studies are showing this to be beneficial and may improve how long a woman lives.

Targeted therapy

Targeted therapy is a newer type of cancer treatment that uses drugs or other substances to identify and attack cancer cells while doing little damage to normal cells. Each type of targeted therapy works differently, but they all attack the cancer cells' inner workings − the programming that makes them different from normal, healthy cells. Bevacizumab (Avastin) is the targeted therapy that has been studied best in ovarian cancer, but other similar drugs, like pembrolizumab, are being looked at, as well.

Catumaxomab is a drug being studied specifically for people with malignant ascites (fluid buildup in the abdomen [belly] caused by cancer cells). It works by targeting 3 different cell types including tumor cells and white blood cells called T-cells.

Poly(ADP-ribose) polymerases (PARPs) are enzymes that have been recently recognized as key regulators of cell survival and cell death. Drugs that inhibit PARP-1 (called PARP inhibitors) have been approved for patients with ovarian cancer caused by mutations in BRCA1 and BRCA2 . New evidence shows that ovarian cancers can also become resistant to treatment with PARP inhibitors. Research is trying to find ways to counteract this process.

Genetic therapies

For ovarian and breast cancers that are caused by the BRCA 1 mutation, it has been shown that low levels of the BRCA 1 mutation are associated with good responses to PARP inhibitors and platinum drugs, like cisplatin and carboplatin. New research shows that microRNA, very small pieces of RNA (substances that carry genetic messages for DNA), can also lower levels of BRCA1 mutations. New drugs that can target these tiny pieces of RNA are being investigated as possible ways to treat these cancers.

Ovarian Cancer Research Highlights

See our latest findings from the ovarian cancer research conducted by our staff researchers & funded through research grants.

The American Cancer Society medical and editorial content team

Our team is made up of doctors and oncology certified nurses with deep knowledge of cancer care as well as editors and translators with extensive experience in medical writing.

Cornelison R, Llaneza DC, Landen CN. Emerging Therapeutics to Overcome Chemoresistance in Epithelial Ovarian Cancer: A Mini-Review. International Journal of Molecular Sciences . 2017;18(10):2171. 

Deraco M, Kusamura S, Virzì S, Puccio F, Macrì A, Famulari C, Solazzo M, Bonomi S, Iusco DR, Baratti D. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy as upfront therapy for advanced epithelial ovarian cancer: multi-institutional phase-II trial. Gynecol Oncol . 2011 Aug;122(2):215-220.

Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361:123-134.

Fu S, Hu W, Iyer R, et al. Phase 1b-2a study to reverse platinum resistance through use of a hypomethylating agent, azacitidine, in patients with platinum-resistant or platinum-refractory epithelial ovarian cancer. Cancer . 2011 Apr 15;117(8):1661-1669.

Heiss MM, Murawa P, Koralewski P, et al. The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: Results of a prospective randomized phase II/III trial. Int J Cancer . 2010 Apr 27.

Khan, S.R., Arshad, M., Wallitt, K. et al. What's New in Imaging for Gynecologic Cancer? Curr Oncol Rep (2017) 19: 85. 

Kwon JS, Tinker A, Pansegrau G, et al. Prophylactic salpingectomy and delayed oophorectomy as an alternative for BRCA mutation carriers. Obstet Gynecol . 2013;121(1):14-24.

Naumann RW, Coleman RL, Burger RA, et al. PRECEDENT: a randomized phase II trial comparing vintafolide (EC145) and pegylated liposomal doxorubicin (PLD) in combination versus PLD alone in patients with platinum-resistant ovarian cancer. J Clin Oncol . 2013 Dec 10;31(35):4400-6. Epub 2013 Oct 14.

Strumidło et al. The potential role of miRNAs in therapy of breast and ovarian cancers associated with BRCA1 mutation Hereditary Cancer in Clinical Practice (2017) 15:15. 

van Driel WJ, Koole SN, Sikorska K et al. Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer. N Engl J Med. 2018 ;378(3):230-240.

Varga A, Piha-Paul SA, Ott PA et al. Pembrolizumab in patients (pts) with PD-L1–positive (PD-L1+) advanced ovarian cancer: Updated analysis of KEYNOTE-028. J Clin Oncol. 2017; 35(15): suppl, 5513-5513.

Last Revised: April 11, 2018

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Current clinical trials underway include:

• Phase II trials evaluating the combination of  pembrolizumab  or  durvalumab , two novel immune therapies, given in combination with chemotherapy, as primary therapy for newly diagnosed and untreated advanced stage ovarian cancer.
• A Phase IB trial to determine the safety and effectiveness of combinations of three targeted therapy drugs in the treatment of recurrent high-grade ovarian cancers.
• The collaborative  WISP (Women Choosing Surgical Prevention) trial  investigating whether preventative surgical removal of only the fallopian tube improves overall quality of life while maintaining reduced risk of developing ovarian cancer. This approach is compared to the standard-of-care, risk-reducing procedure that removes both the fallopian tube and ovaries. This trial is being conducted in partnership with five other cancer research institutions and is funded by the Stand Up to Cancer – Ovarian Cancer Research Fund Alliance – National Ovarian Cancer Coalition (SU2C-OCRFA-NOCC).
• A Phase I study to examine the safety of combining radiotherapy and the PARP inhibitor talazoparib is ongoing. Women who have isolated recurrences from their ovarian cancer may be eligible.

Research Groups and Resources

Gynecologic oncology & reproductive medicine, sprint for life, ovarian quilt project, ovarian cancer research initiatives.

Our commitment to ovarian cancer research is echoed through two major initiatives:

Ovarian Cancer Moon Shot

Our ambitious effort to advance leading-edge care and research, increasing the variety of clinical trials and new treatment options for our patients.

Ovarian Cancer SPORE

Part of a nationwide initiative to accelerate the speed at which ovarian cancer research breakthroughs impact patient outcomes.

We're also making progress in prevention, detection and treatment through ovarian cancer research programs and efforts, including:

Blanton-davis ovarian cancer research program.

The Blanton-Davis Research Program is a multi-disciplinary group of cancer experts focused on targeting all forms of ovarian cancer, including rare tumor types. Our executive committee annually approves funding for specific ovarian cancer research projects that show great promise for improving patient outcomes.

Low-Grade Serous Ovarian Cancer Program

Low-grade serous carcinoma of the ovary (LGSC) is less common and aggressive than high-grade types of ovarian cancer. The Low-Grade Serous Ovarian Cancer Program focuses on cutting-edge laboratory and clinical investigations leading to novel therapies, with the goal of improving outcomes for women with this rare ovarian cancer subtype.

Early Detection & Prevention Effort

Our early detection and prevention effort focuses on developing novel strategies to detect ovarian cancer in its earliest stages. Innovative prevention efforts, especially for high risk women, are also being tested.

Through unique programs and other pioneering research on ovarian cancer, MD Anderson has:

• Implemented a laparoscopic assessment approach to personalize and maximize resection rates of ovarian cancers.
• Developed a two-tier tumor grading system to ensure that patients with serous ovarian cancer are properly treated.
• Demonstrated the importance of limiting the ability of cancer cells to repair damaged DNA, via PARP inhibitors, during treatment.
• Linked chronic stress to the growth and spread of ovarian cancer, which has identified new approaches for potentially blocking cancer growth.
• Led a multi-center effort to develop new strategies for ovarian cancer screening and early detection.
• Developed many targeted and immune therapies that are in various stages of clinical testing.

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Get information on patient appointments, insurance and billing, and directions to and around  MD Anderson .

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Clinical research in ovarian cancer: consensus recommendations from the Gynecologic Cancer InterGroup

Collaborators.

• participants of the 6th Gynecologic Cancer InterGroup (GCIG) Ovarian Cancer Consensus Conference on Clinical Research : Sven Mahner ,  Alexander Reuss ,  Andreas du Bois ,  Christoph Grimm ,  Christian Marth ,  Regina Berger ,  Nicole Concin ,  Ting-Chang Chang ,  Kazunori Ochiai ,  Val Gebski ,  Alison Davis ,  Philip Beale ,  Ignace Vergote ,  Frédéric Kridelka ,  Hannelore Denys ,  Vincent Vandecaveye ,  Francisco Jose Cancido Dos Reis ,  Maria Del Pilar Estevez Diz ,  Gavin Stuart ,  Helen MacKay ,  Mark Carey ,  David Cibula ,  Pavel Dundr Path ,  Oliver Dorigo ,  Jonathan Berek ,  Dearbhaile O'Donnell ,  Abu Saadeh ,  Ingrid Boere ,  Christianne Lok ,  Pluvio Coronado ,  Nelleke Ottevanger ,  David Sp Tan ,  Joseph Ng ,  Antonio Gonzalez Martin ,  Ana Oaknin ,  Andres Poveda ,  Alejandro Perez Fidalgo ,  Alejandro Rauh-Hain ,  Karen Lu ,  Carlos López-Zavala ,  Eva María Gómez-García ,  Isabelle Ray-Coquard ,  Xavier Paoletti ,  Jean-Emmanuel Kurtz ,  Florence Joly ,  Bénédicte Votan ,  Michael Bookman ,  Kathleen Moore ,  Rebecca Arend ,  Keiichi Fujiwara ,  Hiroyuki Fujiwara ,  Kosei Hasegawa ,  Ilan Bruchim ,  Dalia Tsoref ,  Katsutoshi Oda ,  Aikou Okamoto ,  Takayuki Enomoto ,  Dayana Michel ,  Hee-Seung Kim ,  Jung-Yun Lee ,  Asima Mukhopadhyay ,  Dionyssios Katsaros ,  Nicoletta Colombo ,  Sandro Pignata ,  Domenica Lorusso ,  Giovanni Scambia ,  Elise Kohn ,  Jung-Min Lee ,  Iain McNeish ,  Shibani Nicum ,  Laura Farrelly ,  Jalid Sehouli ,  Maren Keller ,  Elena Braicu ,  Line Bjørge ,  Mansoor Raza Mirza ,  Annika Auranen ,  Stephen Welch ,  Amit M Oza ,  Viola Heinzelmann ,  Charlie Gourley ,  Patricia Roxburgh ,  C Simon Herrington ,  Ros Glasspool ,  Rongyu Zang ,  Jianqing Zhu

Affiliations

• 1 Belgium and Luxembourg Gynaecological Oncology Group (BGOG), Leuven, Belgium; University Hospitals Leuven, Leuven, Belgium. Electronic address: [email protected].
• 2 Grupo Español de Cáncer de Ovario (GEICO), Madrid, Spain; Clinica Universidad de Navarra, Madrid, Spain; Program for Solid Tumors at Madrid, and Center for Applied Medical Research (CIMA), Universidad de Navarra, Pamplona, Spain.
• 3 Multicenter Italian Trials in Ovarian Cancer and Gynecologic Malignancies (MITO), Naples, Italy; Fondazione Policlinico Gemelli IRCCS, Rome, Italy.
• 4 Scottish Gynaecological Cancer Trials Group (SGCTG), Cancer Research UK, Edinburgh, UK; Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
• 5 Nordic Society of Gynecologic Oncology Clinical Trial Unit (NSGO-CTU), Copenhagen, Denmark; Rigshospitalet, Copenhagen, Denmark.
• 6 Groupe d'Investigateurs National des Etudes des Cancers Ovariens et du Sein (GINECO), Paris, France; Strasbourg Cancer Institute, Strasbourg, France.
• 7 Japanese Gynecologic Oncology Group (JGOG), Tokyo, Japan; The Jikei University School of Medicine, Tokyo, Japan.
• 8 Gynecologic Oncology Group-Foundation (GOG-F), Philadelphia, PA, USA; OU Health Stephenson Cancer Center, Oklahoma City, OH, USA.
• 9 Belgium and Luxembourg Gynaecological Oncology Group (BGOG), Leuven, Belgium; Centre Hospitalier Universitaire de Liège, Liège, Belgium.
• 10 National Cancer Research Institute (NCRI), London, UK; Department of Surgery and Cancer, Imperial College London, London, UK.
• 11 Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) Study Group, Munich, Germany; Coordinating Center for Clinical Trials, Philipps University, Marburg, Germany.
• 12 Association de Recherche Cancers Gynécologiques (ARCAGY)-GINECO, Paris, France.
• 13 Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) Study Group, Munich, Germany; Kliniken Essen Mitte (KEM), Essen, Germany.
• 14 Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) Study Group, Munich, Germany; University Hospital, Ludwig Maximilians University, Munich, Germany.
• 15 Groupe d'Investigateurs National des Etudes des Cancers Ovariens et du Sein (GINECO), Paris, France; Centre Leon Berard and University Claude Bernard Lyon I, Lyon, France.
• 16 National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
• 17 Women's Cancer Research Network-Cooperative Gynecologic Oncology Investigators (WCRN-COGI), Fresno, CA; Stanford Cancer Institute, Stanford, CA, USA.
• 18 Asia Pacific Gynecologic Oncology Trials Group (APGOT), Seoul, South Korea; Gynecologic Cancer Group Singapore (GCGS), Singapore; Cancer Science Institute, National University of Singapore, Singapore.
• 19 Mario Negri Gynecologic Oncology (MaNGO), Milan, Italy; European Institute of Oncology, Milan, Italy; University of Milano-Bicocca, Milan, Italy.
• 20 Shanghai Gynecologic Oncology Group (SGOG), Shanghai, China; Zhongshan Hospital, Fudan University, Shanghai, China.
• 21 AGO -Austria, Innsbruck, Austria; Kliniken Essen Mitte (KEM), Essen, Germany; Medical University of Innsbruck, Innsbruck, Austria.
• 22 Cancer Trials Ireland (CTI), Dublin, Ireland; St James's Hospital, Dublin, Ireland.
• 23 Global Gynecologic Oncology Consortium (G-GOC), Houston, TX, USA; MD Anderson Cancer Center, The University of Texas, Houston, TX, USA.
• 24 AGO -Austria, Innsbruck, Austria; Medical University of Innsbruck, Innsbruck, Austria.
• 25 Grupo Español de Cáncer de Ovario (GEICO), Madrid, Spain; Hospital Quironsalud, Valencia, Spain.
• 26 Gynecologic Cancer Clinical Trials and Investigation Consortium (GOTIC), North Kanto, Japan; Saitama Medical University International Medical Center, Saitama, Japan.
• 27 Canadian Cancer Trials Group (CCTG), Kingston, ON, Canada; University of British Columbia, Vancouver, BC, Canada.
• 28 Princess Margaret Hospital Consortium (PMHC), Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada.
• 29 Gynecologic Oncology Group-Foundation (GOG-F), Philadelphia, PA, USA; San Francisco Medical Center, San Francisco, CA, USA.
• PMID: 35901833
• PMCID: PMC9465953
• DOI: 10.1016/S1470-2045(22)00139-5

The Gynecologic Cancer InterGroup (GCIG) sixth Ovarian Cancer Conference on Clinical Research was held virtually in October, 2021, following published consensus guidelines. The goal of the consensus meeting was to achieve harmonisation on the design elements of upcoming trials in ovarian cancer, to select important questions for future study, and to identify unmet needs. All 33 GCIG member groups participated in the development, refinement, and adoption of 20 statements within four topic groups on clinical research in ovarian cancer including first line treatment, recurrent disease, disease subgroups, and future trials. Unanimous consensus was obtained for 14 of 20 statements, with greater than 90% concordance in the remaining six statements. The high acceptance rate following active deliberation among the GCIG groups confirmed that a consensus process could be applied in a virtual setting. Together with detailed categorisation of unmet needs, these consensus statements will promote the harmonisation of international clinical research in ovarian cancer.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Publication types

• Research Support, Non-U.S. Gov't
• Carcinoma, Ovarian Epithelial
• Forecasting
• Ovarian Neoplasms* / therapy

Grants and funding

• K08 CA234333/CA/NCI NIH HHS/United States
• Z99 CA999999/ImNIH/Intramural NIH HHS/United States

Journal of Ovarian Research

Article collection: nanotechnological approaches for the treatment of ovarian cancer.

Article Collections

• Most accessed

Development and validation of a prediction model for suboptimal ovarian response in polycystic ovary syndrome (PCOS) patients undergoing GnRH-antagonist protocol in IVF/ICSI cycles

Authors: Xiaohang Xu, Yilin Jiang, Jinlin Du, Haoyue Sun, Xue Wang and Cuilian Zhang

Zinc deficiency deteriorates ovarian follicle development and function by inhibiting mitochondrial function

Authors: Wen-Jiao Liu, Li-Shu Li, Meng-Fan Lan, Jian-Zhou Shang, Jin-Xin Zhang, Wen-Jie Xiong, Xin-Le Lai and Xing Duan

Value of estrogen pretreatment in patients with diminished ovarian reserve and elevated FSH on a line antagonist regimen: a retrospective controlled study

Authors: Lin Lin, Guoyong Chen and Yun Liu

Exosomes in diagnostic and therapeutic applications of ovarian cancer

Authors: Dhaval Bhavsar, Rajeswari Raguraman, Dongin Kim, Xiaoyu Ren, Anupama Munshi, Kathleen Moore, Vassilios Sikavitsas and Rajagopal Ramesh

Examining the oleoylethanolamide supplement effects on glycemic status, oxidative stress, inflammation, and anti-mullerian hormone in polycystic ovary syndrome

Authors: Fatemeh Taghizadeh Shivyari, Hamideh Pakniat, Mohamadreza Rashidi Nooshabadi, Shaghayegh Rostami, Hossein Khadem Haghighian and Mohammad Reza Shiri-Shahsavari

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Possibility of live birth in patients with low serum β-hCG 14 days after blastocyst transfer

Authors: Yixuan Wu and Haiying Liu

Role of CA125 in predicting ovarian cancer survival - a review of the epidemiological literature

Authors: Digant Gupta and Christopher G Lis

A combination of spearmint and flaxseed extract improved endocrine and histomorphology of ovary in experimental PCOS

Authors: Mina Mehraban, Gholamali Jelodar and Farhad Rahmanifar

Rising serum CA-125 levels within the normal range is strongly associated recurrence risk and survival of ovarian cancer

Authors: Szymon Piatek, Grzegorz Panek, Zbigniew Lewandowski, Mariusz Bidzinski, Dominika Piatek, Przemyslaw Kosinski and Miroslaw Wielgos

Biomarkers and algorithms for diagnosis of ovarian cancer: CA125, HE4, RMI and ROMA, a review

Authors: Vincent Dochez, Hélène Caillon, Edouard Vaucel, Jérôme Dimet, Norbert Winer and Guillaume Ducarme

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Editors-in-Chief

Sham S Kakar, University of Louisville, USA

Benjamin K Tsang, University of Ottawa, Canada

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Aims and scope

Journal of Ovarian Research is an open access, peer reviewed, online journal that aims to provide a forum for high-quality basic and clinical research on ovarian function, abnormalities, and cancer. The journal focuses on research that provides new insights into ovarian functions as well as prevention and treatment of diseases afflicting the organ.

Topical areas include, but are not restricted to:

• Ovary development, hormone secretion and regulation
• Follicle growth and ovulation
• Infertility and Polycystic ovarian syndrome
• Regulation of pituitary and other biological functions by ovarian hormones
• Ovarian cancer, its prevention, diagnosis and treatment
• Drug development and screening
• Role of stem cells in ovary development and function

World Ovarian Cancer Day 2024

Join us in commemorating World Ovarian Cancer Day on May 8th with a look back at the most influential articles published in  Journal of Ovarian Research on ovarian cancer in the last few years. 

Journal of Ovarian Research is affiliated with the CROWN initiative, Core Outcomes in Women’s Health. CROWN is an international initiative, led by journal editors, to harmonise outcome reporting in women’s health research. We are coming together to address the widespread, unwarranted variation in reporting of outcomes. CROWN’s main aim is to encourage researchers to report core outcome sets for key conditions in women’s health.

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2022 Citation Impact 4.0 - 2-year Impact Factor 4.7 - 5-year Impact Factor 1.118 - SNIP (Source Normalized Impact per Paper) 0.965 - SJR (SCImago Journal Rank)

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Nih research matters.

July 11, 2011

A Detailed Look at Ovarian Cancer

An analysis of genomic changes in ovarian cancer now provides the most comprehensive and integrated view of cancer genetics for any cancer type to date.

Last year, nearly 22,000 women nationwide were diagnosed with ovarian cancer and about 14,000 women died from it. Ovarian cancer is a complex disease that can arise from various molecular problems. A comprehensive catalog of these potential causes could help researchers develop more targeted and effective treatments. Scientists in The Cancer Genome Atlas (TCGA) Research Network set out to create such a catalog. TCGA is a collaborative effort funded by NIH's National Cancer Institute (NCI) and National Human Genome Research Institute (NHGRI).

The researchers focused on serous adenocarcinoma, the most prevalent form of ovarian cancer, accounting for about 85% of all ovarian cancer deaths. The researchers built upon an approach they used in 2008 to characterize the genome of the most common form of brain cancer. They performed whole-exome sequencing, which examines the protein-coding regions of the genome, on an unprecedented 316 tumors. They also completed other genomic characterizations on these tumors, along with another 173 specimens. The results appeared in the June 30, 2011, issue of Nature .

The researchers found that mutations in a single gene, TP53 , were present in more than 96% of the tumors. TP53 encodes a tumor suppressor protein that normally prevents cancer formation. Two other genes, BRCA1 and BRCA2, were mutated in 22% of the tumors. There were also less frequent mutations in 7 other genes.

The scientists found additional genetic anomalies as well. They identified 113 significant DNA copy number aberrations — differences in the number of copies of specific DNA regions. Modifications to promoter regions, which are known to affect gene expression, were found in 168 genes.

The researchers were able to identify distinct subtypes of the disease. They also detected patterns of gene expression that predict patient survival. Patterns for 108 genes were associated with poor survival and 85 genes with better survival.

To identify opportunities for targeted treatment, the investigators searched for existing drugs that might inhibit the over-expressed genes they identified. They found 68 genes that could be targeted by known compounds, some of which are already approved by the U.S. Food and Drug Administration.

“The integration of complex genomic data sets enabled us to discover an intricate array of genomic changes and validate one specific change that occurs in the vast majority of all ovarian cancers,” says lead author Dr. Paul T. Spellman of the Lawrence Berkeley Lab.

“The new knowledge of the genomic changes in ovarian cancer has revealed that the molecular catalysts of this disease are not limited to small changes affecting individual genes,” says NCI Director Dr. Harold E. Varmus. “Also important are large structural changes that occur in these cancer genomes. Cancer researchers can use this comprehensive body of information to better understand the biology of ovarian cancer and improve the diagnosis and treatment of this dreaded disease.”

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Home » About Ovarian Cancer » Research and Clinical Trials

Ovarian Cancer Research

In collaboration with Stand Up To Cancer and our partner, Ovarian Cancer Research Alliance, NOCC supported the Ovarian Cancer Dream Team – the first of its kind in the history of ovarian cancer research. This outstanding team began its work in July 2015, leveraging collaborative team science.

The SU2C-Ovarian Cancer Research Alliance-National Ovarian Cancer Coalition Dream Team focused on developing new therapies that target DNA repair and expanding PARP inhibitor use to women even beyond those with BRCA mutations. The team aimed to identify women at increased risk for ovarian cancer by screening for inherited mutations in genes linked to DNA repair, enabling these high-risk women to choose lifesaving preventative measures. Learn more about the SU2C-Ovarian Cancer Research Alliance-National Ovarian Cancer Coalition Dream Team.

In 2012, NOCC partnered with the GOG (Gynecologic Oncology Group) in funding the LIvES Study, overseen by the University of Arizona Cancer Center. The LIvES research initiative focused on a randomized, controlled trial study to test hypotheses relating dietary intake and physical activity to improved progression-free survival and quality of life among women diagnosed with ovarian cancer.

In 2011, NOCC partnered with Ovarian Cancer Research Fund (OCRF) and funded “The Ann Schreiber Ovarian Cancer Research Training Program of Excellence: A Study by Dr. Ruth Perets”.

Working to Improve Outcomes

Clinical trials lead to new and improved standards of care for ovarian cancer. For anyone who chooses to join a clinical trial, they will receive the best care available and help themselves as well as others by contributing to research.

What is an ovarian cancer clinical trial? Why should I consider participating?

Clinical trials are research studies designed to find ways to improve health, answer scientific questions and find better ways to prevent, diagnose or treat cancer. For many women with ovarian cancer, investigational treatments may offer new hope. Through participation in these trials, patients may receive access to new therapy options that are not available beyond the clinical trial setting.

Clinical trial phases

There are four main phases of clinical trials. This allows researchers to ask and answer questions as the trial progresses to ensure their information is reliable and protects the patient.

Phase I: Researchers first test a new drug or treatment in a small group (20-80) to evaluate its safety, determine safe dosages and identify side effects.

Phase II: The study drug or treatment is given to a larger group (100-300) to see if it’s effective and to further evaluate its safety; often, new combinations of drugs are tested.

Phase III: Large groups (1,000-3,000) are given the study drug or treatment to confirm its efficacy, monitor side effects, compare it to commonly used treatments and collect information that will allow the drug or treatment to be used safely. Usually, patients are put into at least two groups – a standard group and an unspecified group, known as randomization . 

Phase IV: This focuses on long-term effectiveness and side effects of drug or treatment post-FDA approval, and is conducted over an extended period of time.

Myths and misconceptions about clinical trials

Questions to ask about clinical trials:.

It’s advisable to bring a family member or friend  along to learn about a clinical trial. Ask them to take notes and step in with questions if needed, such as:

• Is a clinical trial a treatment option for me?
• Why is the study being done?
• Who’s running it?
• Am I eligible to participate?
• What phase is the clinical trial in?
• What are the benefits and risks?
• Will my insurance cover the costs?
• How long will the study last?
• Will you still be my oncologist?
• What is informed consent?
• What are my rights as a patient?  Can I leave the trial at any time?

Will I get a placebo?

No. Clinical trials test the safety and benefits of new treatments as well as new combinations (or new doses) of standard treatments. You will get either the new treatment and/or the standard treatment. Sometimes, patients get the standard treatment plus a placebo rather than the standard treatment plus the new treatment (being studied).

Will my insurance cover the cost?

A growing number of states have passed legislation or instituted special agreements requiring health plans to pay the cost of routine medical care received by a participant in a clinical trial. Learn more about paying for clinical trials.

Types of trials

Treatment trials.

These test the effectiveness of new treatments or ways of using existing treatments in people with cancer. Combinations of different treatment types may also be tested. Treatment trials can include new drugs or new combinations of current drugs, new surgery or radiation therapy techniques. They are also used to test vaccines or other therapies that stimulate the immune system to fight cancer. 

Screening trials

These trials are conducted to find new ways to detect cancer, especially in the early stages.

Quality-of-life trials

These examine ways to increase the level of health and comfort for cancer patients.

How do I find a clinical trial?

If you are thinking about joining a clinical trial as a treatment option, the best place to start is to talk with your doctor or another member of your health care team. Often your doctor may know about a clinical trial that could be a good option for you. He or she may also be able to search for a trial for you, provide information, and answer questions to help you decide about joining a clinical trial.

You can typically find the most recently updated listing of clinical trials online:

• Clinicaltrials.gov is a resource provided by the U.S. National Library of Medicine; it is a database of privately and publicly funded clinical studies conducted around the world
• Centerwatch.com is a clinical trials listing service for ovarian cancer medical research trials actively recruiting patients
• Emergingmed.com Clinical Trial Navigation Service can assist in looking for clinical trials by filling a short questionnaire

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Current research into ovarian cancer

For the past 120 years, we’ve been making discoveries that have saved countless lives. But we have so much more to do. Our strategy sets out how we'll accelerate progress towards a better future.

Saving lives through our research

From developing viruses as treatments, to leading clinical trials for women whose cancer has come back – our scientists are working hard to improve outcomes for women with ovarian cancer. Below are some examples of what our researchers are doing right now.

Our current researchers

Developing new treatments

In London, Professor Fran Balkwill is studying how healthy cells in ovarian tumours are turned ‘bad’ by the cancer cells around them. Understanding how to turn these ‘bad’ cells back into ‘good’ ones could lead to new drugs and treatments for the disease.

Testing new drug combinations

Dr Shibani Nicum is leading the ICON9 clinical trial, which is seeing if treating people with a combination of two drugs called olaparib and cediranib could improve outcomes for patients whose cancer has come back after treatment. If shown to be effective, this new treatment could become the standard of care for people with relapsed ovarian cancer.

Developing cancer blood tests

Specific faults in how DNA is repaired can make tumours more sensitive to treatment. Dr James Brenton in Cambridge is developing ways to detect patterns of faults in ovarian tumours. He’s also developing blood tests that could quickly predict whether patients are responding to treatment. This could help doctors choose the best treatment for each patient and help us understand why many ovarian cancers come back after treatment.

Personalising cancer risk prediction

Professor Antonis Antoniou and his collaborators, in Cambridge, are developing a tool called CanRisk to predict people’s risk of getting ovarian, breast and prostate cancer by combining genetic, lifestyle and hormonal risk factors. Accurately predicting cancer risk will mean people at high cancer risk can be monitored more closely, to catch the disease earlier, when treatment is more likely to be effective. It will also help in identifying those who will benefit most from prevention options, such as risk-reducing surgery or risk-reducing medication.

Further information

Past research.

Thanks to research, we've helped change the outlook for women with ovarian cancer.

Patients' stories

Meet people like Amanda who have experienced first-hand how our research is making a difference. The life-saving research we do wouldn’t be possible without your support.

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• Published: 05 October 2021

Next steps in the early detection of ovarian cancer

• Robert C. Bast 1 ,
• Chae Young Han 1 ,
• Zhen Lu 1 &
• Karen H. Lu 2  

Communications Medicine volume  1 , Article number:  36 ( 2021 ) Cite this article

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• Diagnostic markers
• Ovarian cancer

A recent ovarian cancer screening trial found no reduction in mortality, despite increased detection of early stage disease. Here, we discuss these findings and examine next steps to develop more effective approaches for the early detection of ovarian cancer.

Ovarian cancer afflicts more than 300,000 women each year worldwide. Despite improved care with cytoreductive surgery and combination chemotherapy, the majority of patients will die from their disease. When cancer is limited to the ovaries in stage I, up to 90% of patients can be cured with currently available treatment 1 . Even when disease has spread to pelvic organs in stage II, up to 70% survive for more than 10 years. With further spread over the surface of the abdominal cavity (stage III) or outside the abdomen (stage IV), long term survival is reduced to 20% or lower. Approximately 25–30% of patients are currently diagnosed in stage I or II. It has long been assumed that increasing the fraction of women with ovarian cancer detected at an early stage could improve survival and decrease mortality.

The negative outcome of the UKCTOCS calls into question where we should go next to find an effective strategy for early detection of ovarian cancer.

The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

The UKCTOCS, the largest ovarian cancer screening trial conducted to date, randomized postmenopausal women at average risk for developing ovarian cancer to a control group (101,314), annual transvaginal sonography (TVS) for 7 years (50,623), or “multi-modal screening” for 7 years (50,625) involving a “two-step process”, where changes in annual CA125 ovarian tumor biomarker blood tests were analyzed with a Bayesian Risk of Ovarian Cancer Algorithm (ROCA) prompting TVS in a small fraction of patients with a significant increase in CA125 2 . Executing a screening study of this magnitude constitutes a remarkable achievement. In the initial report in 2016, there was no significant reduction in mortality overall, but a 20% reduction was found in a pre-specified subset of women with incident disease who had been diagnosed after 7 years of screening on the multi-modal arm ( p  = 0.021). Given wide statistical bounds around the estimate, re-analysis was planned after 5 years of additional follow-up. The update confirmed a stage shift with an increase in early stage disease and a decrease in late stage disease in the screened population, but failed to confirm a reduction in mortality 1 .

Failure to sustain a mortality advantage despite an increase in early stage disease could relate to inadequate therapy. As collaborating sites were chosen for expertize in gynecologic oncology, surgery is likely to have been state-of-the-art. It would be important to know that all early stage patients received six cycles of carboplatin and paclitaxel. If the choice and duration of chemotherapy were at the discretion of collaborating oncologists, some might have chosen single agent carboplatin or used only three cycles of combination chemotherapy for early stage disease.

Early stage (I/II) disease detected in the multimodal arm of the UKCTOCS was associated with increased mortality, consistent with the possibility that rising CA125 detected additional micro-metastatic disease or identified visible tumors that resisted conventional chemotherapy. While PARP-inhibitor maintenance therapy is generally prescribed for advanced stage (III/IV) disease, patients with screen-detected homologous repair deficient early stage (I/II) ovarian cancer might also benefit. Novel agents, including SIK2 inhibitors 3 , are being developed to enhance primary treatment with carboplatin and paclitaxel potentially improving care for both early and late stage disease.

Furthermore, the magnitude of the stage shift observed in the UKCTOCS may not have been sufficient to reduce mortality. The fraction of stage I/II patients in the UKCTOCS increased from 28.4% with no screening to 38.1% with CA125 followed by TVS. The fraction of patients with stage IV disease decreased from 20.7 to 15.1%. A much greater stage shift was observed in the single arm Normal Risk Ovarian Screening Study (NROSS) that has been conducted, in parallel, over the last 19 years in post-menopausal women at average risk in the United States, using the identical two-step multi-modal screening plan with the CA125 based ROCA followed by TVS. Among the 7597 women screened, 16 epithelial ovarian cancers have been detected—2 were borderline and 14 invasive—with 11 (69%) in early stage (I or II) (updated from ref. 4 ). One of 16 cases (6%) was detected in stage IV. Both trials confirmed that adequate specificity could be attained with the two-step strategy, requiring no more than 2–4 operations to detect each case of ovarian cancer. The reason for a greater stage shift in the smaller trial is not clear. This could reflect statistical variation with the smaller size of the NROSS. Difficulties were, however, encountered with TVS imaging in the UKCTOCS. In a retrospective review of 1000 archived cases, ovaries and fallopian tubes could be identified in only 50% of cases 5 . TVS imaging could have been more reliable in the NROSS. Another difference between the trials relates to processing of blood for measurement of CA125. In the NROSS, blood was drawn in glass tubes without gel, serum was separated and frozen on the same day, while in the UKCTOCS blood was drawn in gel separation tubes, shipped at ambient temperature and separated after up to 56 h. A modest systematic reduction in CA125 levels in the UKCTOCS could have decreased the ability to detect early stage disease. In addition, particular care was taken in the NROSS to follow elevations of CA125 with repeated TVS and to minimize time to surgical intervention.

The negative outcome of the UKCTOCS calls into question, where we should go next to find an effective strategy for early detection of ovarian cancer. While some might suspend attempts to detect early stage ovarian cancer awaiting a novel and disruptive technology, the two-step screening strategy has already achieved adequate specificity and a clear stage shift, although sensitivity is not yet adequate. There are opportunities for improvement both in serum biomarkers and in imaging. Only 80% of ovarian cancers express CA125 and serum levels of CA125 are elevated in only 70% of stage I/II cancers. A recent review identified 35 biomarkers that complement CA125 and could potentially improve sensitivity of the initial step in screening 6 . A combination of CA125, HE4, and CA72.4 detects 16% of cases missed by CA125 7 . Through a collaboration sponsored by the NCI Early Detection Research Network (EDRN), CA125 detected 72% of early stage cases at 98% specificity, whereas a combination of CA125, HE4 antigen-autoantibody complexes 8 and osteopontin 9 detected 89% at 94% specificity 10 . A second-generation ROCA algorithm is being developed and can be tested prospectively for specificity in the NROSS cohort.

In addition to detecting a greater fraction of early stage patients, panels of biomarkers could improve lead time with detection of cancers at longer intervals before clinical presentation. Autoantibodies could arise in response to very small volumes of early disease, which would be particularly important for high grade serous lesions arising from the fallopian tube. Anti-p53 autoantibodies have been detected in more than 20% of patients with early and late stage ovarian cancer 11 . Assaying serum samples from the UKCTOCS, titers of anti-p53 autoantibodies increased 8 months before elevation of CA125 and 22 months prior to clinical presentation in patients who did not exhibit increases in serum CA125 12 . This is the first of >120 biomarkers tested by our group that increased lead time over CA125. Among 19 promising autoantibodies tested, anti-p53, anti-CTAG1, and anti-IL-8 detected the greatest fraction of early stage ovarian cancer patients 11 .

A variety of additional biomarkers are being developed to detect ovarian cancer including ctDNA, methylated DNA, and miRNAs. Alterations in cervical and peripheral blood ctDNA can complement CA125 in detecting early stage disease 12 . While ovarian cancer has been included in DNA-based pan-cancer screening strategies 13 , 14 , detecting stage I/II disease has proven challenging. Future research should optimize the integration of DNA and protein biomarkers.

Whatever the biomarker panel chosen, screening could be performed more frequently. In patients at high risk, largely related to germ-line BRCA1/2 mutations, screening with the ROCA every 3 months proved more effective than annual screening 15 , 16 , While it is difficult to imagine more frequent screening for ovarian cancer alone in patients at conventional risk, blood might be drawn every six months to screen for multiple cancers in women over 50. Ovarian cancer screening could be paired with DNA-based pan-cancer screening strategies or combined with site-specific blood tests that are being developed to detect colorectal adenomas, and breast and pancreatic cancers 17 .

Imaging, the second step in two-stage screening, poses perhaps the greatest unmet need. As a single modality, TVS lacks adequate sensitivity and specificity for early detection of ovarian cancer. The majority of high-grade serous cancers probably arise in the fallopian tubes. Even in expert hands, fallopian tubes could not be imaged in 23% of 549 healthy women 18 . CT, PET-CT, and MRI also have problems with sensitivity, specificity, exposure to radiation and cost for screening 7 .

One possible solution in patients with rising serum biomarkers and negative TVS is falloposcopy, where a fiberoptic scope is threaded through the uterus and fallopian tube to visualize the fimbriae and ovary. This would be particularly relevant for women with BRCA1/2 mutations who are delaying risk reducing surgery. The EDRN is currently evaluating the feasibility of this approach. Another technology that is being developed is superconducting quantum interference detection (SQUID), which is a sensitive method for detecting faint magnetic fields. Anti-CA125 antibodies have been conjugated with ferritin nanospheres. Only antibody conjugated nanospheres bound to cells are detected by magnetic relaxation. Ex vivo, 10 6 ovarian cancer cells (0.1 mm) can be detected 7 . If uptake of antibody-coated nanospheres can be optimized in xenografts, this approach might be utilized to detect recurrent ovarian cancer and then tested in healthy women with rising biomarkers and negative TVS.

Conclusions

Given the specificity of the two-step screening strategy, opportunities to improve both phases and the impressive stage shift in the CA125-based NROSS trial, further development of this approach appears worthy of pursuit. The potential benefit for ovarian cancer patients is substantial. Computer simulations suggest that an effective strategy for early detection could reduce mortality by 10–30%, a dramatic improvement over our current attempts to improve therapy 7 .

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Acknowledgements

This work was supported by funds from the NCI Early Detection Research Network (5 U01 CA200462-02, RCB), the MD Anderson Ovarian SPOREs (P50 CA83639 and P50CA217685, R.C.B.), National Cancer Institute, Department of Health and Human Services; the Cancer Prevention Research Institute of Texas (RP160145, R.C.B.); Golfer’s Against Cancer; the Tracey Joe Wilson Foundation; and generous donations from the Ann and Henry Zarrow Foundation, the Mossy Foundation, the Roberson Endowment, Stuart and Gaye Lynn Zarrow, Barry and Karen Elson, and Arthur and Sandra Williams.

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R.C.B. wrote the commentary. C.Y.H., Z.L., and K.H.L. contributed data and reviewed the manuscript.

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Bast, R.C., Han, C.Y., Lu, Z. et al. Next steps in the early detection of ovarian cancer. Commun Med 1 , 36 (2021). https://doi.org/10.1038/s43856-021-00037-9

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Penn Medicine at the 2024 ASCO Annual Meeting

May 23, 2024.

CHICAGO –  Researchers from Penn Medicine’s Abramson Cancer Center (ACC) and the Perelman School of Medicine at the University of Pennsylvania will present data on the latest advances in cancer research at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting , happening May 31—June 4, 2024 in Chicago and online. Follow @PennMedicine and @PennMDForum for updates.

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Experts from Penn Medicine are available to comment on a wide range of cancer research and care topics before, during, and after the meeting by video call, phone, or email. To arrange interviews, please contact Meagan Raeke at [email protected] or 267-693-6224.

ASCO leaders from Penn Medicine

Lynn M. Schuchter, MD, FASCO , the Madlyn and Leonard Abramson Professor of Clinical Oncology and director of the Tara Miller Melanoma Center , is the 2023-2024 ASCO President, and the ASCO Annual Meeting program features more than 200 sessions complementing her Presidential Theme: The Art and Science of Cancer Care: From Comfort to Cure . Schuchter’s experiences treating patients over a three-decade career at Penn informed the development of her patient-centered theme for the meeting.

In addition, Angela DeMichele, MD, MSCE, FASCO , the Mariann T. and Robert J. MacDonald Professor in Breast Cancer Research, is the chair of the Scientific Program Committee; Charu Aggarwal, MD, MPH, FASCO , the Leslye M. Heisler Associate Professor for Lung Cancer Excellence, is the chair of the Cancer Communications Committee and an incoming elected member of the Nominating Committee; and Neha Vapiwala, MD, FASCO , a professor of Radiation Oncology, is an elected member of the Nominating Committee.

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Key Presentations

Penn researchers will present results from clinical trials, including a national cooperative group study for esophageal cancer , a Phase I study using a new CAR T cell therapy for re-treatment in patients with lymphoma , and a multicenter study of a combination therapy for ovarian cancer . They will also present results from several studies that show how AI is being applied to cancer care.

Treatment clinical trials

• Phase II study of combination therapy for recurrent ovarian cancer ( Abstract 5510 ). Currently, no treatment alternatives to chemotherapy exist for ovarian cancer that returns after standard platinum chemotherapy. According to the Ovarian Cancer Research Alliance, around 70 percent of patients diagnosed with ovarian cancer will have a recurrence. This investigator-initiated multi-center clinical trial, led by Fiona Simpkins, MD , the Hilarie L. and Mitchell L. Morgan President's Distinguished Professor in Women's Health, assessed a new strategy combining two different targeted therapies—an ATR inhibitor and a PARP inhibitor—for patients with recurrent ovarian cancer. The combination therapy was safe, and nearly half of the patients saw some tumor shrinkage, with an overall response rate of 48.5 percent and median progression-free survival of 8.3 months. Simpkins will present the findings in a Clinical Science Symposium on Saturday, June 1 at 1:15 p.m. CT in Room E451.
• Phase I first-in-human study using armored CAR T for lymphoma ( Abstract 7004 ). While CAR T cell therapy has revolutionized treatment for many blood cancers, most patients who receive an FDA-approved CAR T cell therapy product do not experience a long-term remission . T hose who relapse after CAR T cell therapy tend to have a poor prognosis. This Phase I study, led by Jakub Svoboda, MD , an associate professor of Hematology-Oncology, aims to find a new treatment option for these patients. The study tested a new armored CAR T, developed by Carl June, MD , the Richard W. Vague Professor in Immunotherapy, that secretes interleukin 18 (IL 18) in addition to targeting CD19. The new CAR T cell therapy was safe, with a three-month overall response rate of 80 percent in 20 patients with non-Hodgkin lymphoma (NHL) whose cancers relapsed or did not respond after receiving a commercially available CAR T cell therapy. Some of the earliest patients treated have now been in remission for two years or more. Svoboda will present the research in an Oral Abstract Session on Saturday, June 1 at 3 p.m. CT in S100bc .
• Phase II/III ECOG-ACRIN study of pre-surgery immunotherapy for esophageal cancer ( Abstract 4000 ). The current standard of care treatment for patients with localized esophageal and gastroesophageal junction cancer is chemotherapy and radiation before surgery. Since immunotherapy has proved beneficial for patients with advanced disease, this study assessed whether adding immunotherapy to chemotherapy and radiation could improve pathologic complete response (pCR) at surgery for patients with less-advanced esophageal cancer. This Phase II/III ECOG-ACRIN study ( EA2174 ), led by Jennifer R. Eads, MD , physician lead for GI Clinical Research and an associate professor of Hematology-Oncology, found that adding immunotherapy did not help eradicate the tumors, with a pCR rate of 21 percent in the group who did not receive immunotherapy, compared to 24.8 percent in the group who did, a difference that was not statistically significant. The results could help inform future clinical trial design for this patient population. Eads will present the study results in an Oral Abstract Session on Tuesday, June 4 at 9:45 a.m. CT in Hall D1 .

AI in cancer care

• Deep learning CT-imaging based biomarker to predict immunotherapy response in lung cancer ( Abstract 102 ). One of the challenges to determining whether someone with non-small cell lung cancer (NSCLC) will benefit from immunotherapy is that a tissue biopsy is required to determine the PD-L1 status, the most common—yet still imperfect—biomarker of response. In this study, Ravi Parikh, MD , an assistant professor of Medicine and Health Policy, and colleagues, used a deep-learning model to develop a biomarker based on data from patient CT scans, which are widely used and more readily available than tissue biopsies. The team trained the model on nearly 20,000 patient scans from nine different institutions and validated it in two different datasets: one including more than 450 scans from patients treated at 10 different institutions, representing ‘real world’ data, and a smaller data set from a Phase I clinical trial. The model was accurately able to predict “high responders” with a three times greater likelihood of progression-free survival than those the model identified as “low responders,” independent of PD-L1 status. Parikh will present the findings in a Clinical Science Symposium on Saturday, June 1 at 8 a.m. CT in Hall D1.
• BE-a-PAL: A randomized trial of algorithm-based default palliative care referral among patients with advanced cancer ( Abstract 12002 ). Previous work also led by Parikh has shown that machine-learning triggered ‘nudges’ to prompt advanced care planning conversations can improve end-of-life care for patients with cancer. Building off that research, this study used an algorithm to identify patients with certain stage 3 or 4 cancers who could benefit from a palliative care consultation at 15 outpatient clinics in a large community oncology network. In the intervention arm, a palliative care consultation was automatically initiated via the electronic medical record. The intervention arm resulted in more than triple the number of palliative care consultations and less than half the rates of end-of-life chemotherapy—which is universally recognized as low-quality care—compared to the control arm. Parikh will present the findings in an Oral Abstract Session on Sunday, June 2 at 8 a.m. CT in Room S100a.
• National implementation of an AI-based virtual dietitian for patients with cancer ( Abstract 1500 ). Penn medical student Keshav Goel, who is interning with personalized nutrition technology company, Savor Health, shares results from the company’s rollout of an AI-based virtual dietitian for patients with cancer. Research shows that many cancer patients who seek nutrition support do not receive it. This virtual platform was designed to address those needs and implemented nationally with 25 cancer advocacy organizations. More than 3,300 users registered for the platform, with 94 percent satisfaction, 84 percent reporting actively using the nutrition advice to guide their diets, 82 percent reporting improved quality of life, and among those with high symptom burden, 88 percent feeling that the platform helped them manage their symptoms. Goel will present the research in an Oral Abstract Session on Tuesday, June 4 at 9:45 a.m. CT in Room S100bc .

Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, excellence in patient care, and community service. The organization consists of the  University of Pennsylvania Health System and Penn’s  Raymond and Ruth Perelman School of Medicine , founded in 1765 as the nation’s first medical school.

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Cancer Center experts present research at national conference

Ovarian and blood cancer trials highlight uc’s asco abstracts.

University of Cincinnati Cancer Center experts will present research at the American Society of Clinical Oncology annual meeting May 31 to June 4 in Chicago.

Platform-predicted treatment leads to longer survival for patients with ovarian cancer

Thomas Herzog, MD. Photo/University of Cincinnati Cancer Center.

After an initial response to chemotherapy, many patients with ovarian cancer encounter a period of resistance to therapy that can lead to tumor regrowth. 

The Cancer Center’s Thomas Herzog, MD, said this resistance is believed to be partially caused by cancer stem cells (CSCs) that rebuild and repair tumors after chemotherapy. In a recent trial, researchers used a diagnostic tool called ChemoID that determines how sensitive CSCs and bulk tumor cells are to various cancer-killing therapies.

“The goal of the test is to find the most effective chemotherapeutic agents that would reduce CSCs in ovarian cancer, thereby limiting recurrent disease potential to help improve patients’ outcomes,” said Herzog, a University of Cincinnati Cancer Center member, the Paul and Carolyn Flory Professor in Gynecologic Oncology in the UC College of Medicine, and director of UC Health’s Gynecologic Cancer Disease Center. “ChemoID provides a prioritized list of effective and ineffective chemotherapies after taking a tissue biopsy of the tumor.”

In a multisite clinical trial, patients with recurrent platinum-resistant epithelial ovarian cancer were randomized to have their chemotherapy regimens selected through the ChemoID platform or by their physician’s best choice. 

Patients in the physician-choice arm had an overall response rate to their chemotherapy of 5%, while those in the ChemoID arm had a 55% overall response rate. The median progression-free survival, or time after treatment when the disease does not get worse, was three months for the physician-choice group and 11 months for the ChemoID group.

Moving forward, Herzog said a larger trial will be needed to validate these results.

Herzog will present the oral abstract  Relationship of cancer stem cell functional assay and objective response rate of patients with recurrent platinum-resistant ovarian cancer in a randomized trial  June 1 from 8-9:30 a.m. Co-authors include Thomas Krivak, John Diaz, Scott Lentz, Stephen Bush, Navya Nair, Nadim Bou Zgheib, Camille Gunderson Jackson, Abhijit Barve, Seth Lirette, Candace Howard, Jagan Valluri, Krista Denning and Pier Paolo Claudio. 

Herzog will also present the poster  Endometrial cancer (EC) by ERBB2 amplification (ERBB2amp) status: Differences in molecular subtypes, ancestry, and real-world outcomes  June 3 from 9 a.m. to 12 p.m. Co-authors include Natalie Danziger, Douglas Lin, Julia Elvin, Andrew Kelly, Ryon Graf, Robert Coleman, Bhavana Pothuri, Ramez Eskander, Julia Quintanilha and Brian Slomovitz. 

Trial tests drug’s ability to overcome resistance in lymphoma

The Cancer Center’s John Byrd, MD, will present information on a Phase 1 trial testing a new treatment for patients with non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL) whose cancer has returned or stopped responding to treatment (relapsed/refractory).

On average, about a quarter of patients with NHL or CLL will relapse by 24 months. Each patient is unique, and the relapse can occur with different mutations, including a MALT mutation that promotes survival and proliferation of blood cancers.

Cancer cells can also sometimes develop resistance to currently-used drugs targeting other enzymes, creating the need for innovative new therapies. 

The trial drug, ONO-7018, targets a protein called MALT1. Preclinical data showed the drug inhibits MALT1 activity and exhibited an antitumor effect with a good safety profile, giving it therapeutic potential to be effective and overcome resistance.

Erin Hertlein, PhD, left, and John Byrd, right, look at data in the Leukemia and Drug Development Lab. Photo/UC Foundation.

In the trial, patients will be given ONO-7018 orally in 21-day treatment cycles. The first group of up to 48 patients will be enrolled to receive increasing doses until the maximum tolerated dose is identified. Once this occurs, a second group of up to 60 patients will be enrolled to receive the optimal dose identified.

“We are excited to have this exciting new agent, ONO-7018, available for our patients with NHL and CLL who have exhausted available effective therapies available for their disease,” said Byrd, Gordon and Helen Hughes Taylor Professor and Chair of the Department of Internal Medicine at the UC College of Medicine. “MALT1 is an exciting target across all B-cell malignancies and potentially for other types of cancer.” 

The trial, which is currently recruiting patients, will primarily assess the drug’s safety and tolerability.

Byrd will present the poster  A phase I, first-in-human study of ONO-7018 in patients with relapsed/refractory non-Hodgkin lymphoma or chronic lymphocytic leukemia  June 3 from 9 a.m. to 12 p.m. Co-authors include Pierluigi Porcu, Thomas Sundermeier, Takashi Nakada, Takeyuki Iwata, Sergio Prados and Leo Gordon. 

For more information on this and other blood cancer clinical trials at the Cancer Center, contact Michelle Marcum at [email protected] or 513-584-6628.

Research examines link between sleep disturbance and cancer-related cognitive impairment

Cancer-related cognitive impairment (CRCI), often called “chemo brain,” affects approximately 75% of individuals with cancer.

The Cancer Center’s cognitive clinical registry found that more than 83% of patients report experiencing sleep disturbances, leading researchers to ask the question of how sleep disturbances and sleep apnea contribute to CRCI.

“CRCI is complex and overlaps with risk factors associated with non-cancer cognitive impairment and neurodegenerative disease,” said Alique Topalian, PhD, a research scientist in Survivorship and Supportive Services at the Cancer Center. “Sleep is central to maintaining brain health. Understanding the relationship between sleep and cancer is important for mitigating CRCI and neurodegenerative disease.”  

In patients who do not have cancer, impaired sleep contributes to executive dysfunction and enlarged brain ventricles, which disrupt cerebral spinal fluid (CSF) flow and drainage of waste material from the brain, Topalian said. The team hypothesized this same process may be a contributing factor to CRCI.

“Reduced removal of toxic byproducts of normal brain metabolism and inflammation that is induced by cancer and its treatment could explain one mechanism of action for CRCI and the increased risk of neurodegenerative disease in cancer survivors,” Topalian said.

A Cancer Center team will present findings on how sleep disturbances and sleep apnea affect cancer-related cognitive impairment. Photo/iStock/FG Trade.

The research team analyzed data from 135 patients in the cognitive clinic’s clinical registry and found sleep apnea and sleep disturbances to be highly prevalent in CRCI. 

“There was a statistical trend toward a relationship between sleep disturbance severity in CRCI and enlarged ventricles,” Topalian said. “Sleep disturbances did not correlate with measures of cognitive impairment. However, ventricular size was significantly associated with impaired processing speed, sustained attention/inhibitory control and semantic fluency.”

Topalian said the novel finding of enlarged brain ventricles in these patients suggests treatment aimed at improving sleep disturbances may help regulate disrupted CSF flow, which could potentially improve CRCI cognitive symptoms.

“We are pursuing fundings for a CPAP and sleep health treatment trial for CRCI patients to investigate how treatment impacts cognitive, imaging and serum markers of CSF flow,” she said.

Additionally, the research team plans to form an ongoing translational working group to expand research on this topic.

Research assistant Sophie Kushman will present the poster “ Sleep apnea and glymphatic dysfunction as a mediator of executive dysfunction and neurodegenerative risk in cancer related cognitive impairment (CRCI) ” during the Symptom Science and Palliative Care session June 3 from 1:30 to 4:30 p.m. Abstract co-authors are Topalian and Rhonna Shatz, DO.

Unique approach aids elementary science education

As the University of Cincinnati Cancer Center is tackling how to reduce the suffering and mortality of cancer in the community today, it is also testing unique ways to encourage the next generation of cancer researchers.

William Barrett, MD, co-director of the Cancer Center, professor and chair of Radiation Oncology in UC’s College of Medicine, and medical director of the Barrett Center for Cancer Prevention, Treatment and Research, said elementary students, particularly those in socially and financially disadvantaged settings, encounter barriers to effective scientific learning. 

With an aim to overcome these barriers, which include maintaining interest, concentration and focus, Barrett and his colleagues implemented a scientific educational program for children attending an urban community center’s after-school program. 

During the program’s activities, five students at a time complete three-minute sessions at tutoring stations on human physiology, astronomy, geography, geology and cancer led by medical students or residents. Meanwhile, another group of five students goes through three-minute basketball drills with a coach on the court. 

Cancer Center volunteers developed a scientific educational program that alternated basketball drills with educational stations at a community center's after-school program. Photo/Nik Shuliahin/Unsplash.

The groups alternate between basketball and tutoring until all students have participated in all five drills and tutoring stations. Then the kids are quizzed on what they learned, and an end-of-practice scrimmage begins with a score based on the quiz results.

“Within weeks, nearly every child could list the planets of the solar system in order; calculate  their pulse and explain its importance; list the most common symptoms of the most prevalent cancers; correctly identify continents, oceans, countries and states on maps; and explain the origin of volcanoes, earthquakes, hurricanes and tsunamis,” Barrett and his coauthors wrote in the abstract.

The alternating of physical exertion with learning appears to maintain interest, focus and concentration, and the approach could be widely applied to students from diverse backgrounds.

Barrett is first author on the abstract  Defeating cancer through education, prevention, and youth athletics.  Sherwin Anderson, Andrew Frankart, Samuel Thompson and William Mackey are co-authors.

Impact Lives Here

The University of Cincinnati is leading public urban universities into a new era of innovation and impact. Our faculty, staff and students are saving lives, changing outcomes and bending the future in our city's direction.  Next Lives Here.

Featured photo at top of ovarian cancer cells. Photo/OGPhoto/iStock.

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OCRA’s 2024 Grantees: Health Equity Research Grants

OCRA’s Health Equity Research Grants for 2024 are dedicated to advancing equity in care of ovarian and related gynecologic cancers, addressing deep disparities in early diagnosis, access to care, and patient outcomes.

“In a year of remarkable new research being undertaken by OCRA-funded scientists, our expanded focus on health equity is more critical than ever,” says Audra Moran, OCRA’s President & CEO. “Disparities in care are felt across the patient sector and have wide impact. We need to resolve these known issues and ensure that as new diagnostic tools and treatments come to the field, they are accessible and available to all patients who can benefit from them.”

Dr. Emily Ko, University of Pennsylvania OCRA’s Health Equity Research Grant, Sponsored by GSK

▶ Implementing a patient supportive program that will  address practical barriers to receiving optimal care , such as financial strain, transportation, and emotional support, with the aim of ensuring equitable care for all gynecologic cancer patients. Sponsorship for OCRA’s first-ever Health Equity Research Grant was provided by GSK.

Dr. David Shalowitz, West Michigan Cancer Center OCRA’s Health Equity Research Grant

▶ Developing a clinician-to-clinician telemedicine program to enable rural doctors to consult with gynecologic oncology specialists, with the goal of  increasing access to high-quality care for patients in remote areas , reducing the need for long-distance travel, and ultimately improving patient outcomes. 

Dr. Judith Walsh, University of California – San Francisco OCRA’s Health Equity Research Grant

▶ Conducting a qualitative study with a diverse, multi-ethnic cohort, to identify barriers and facilitators to early ovarian cancer diagnosis, seeking to improve public health messaging and  reduce disparities in ovarian cancer early diagnosis .

Act Now: Ensure Equitable Access to Multi-Cancer Early Detection Tools New diagnostics are emerging with potential to improve early detection of cancers like ovarian cancer.  Contact your representatives now, so when these tools are approved by the FDA, Congress can ensure vulnerable populations have equitable access .

Posted on May 28, 2024 in Research Tags: OCRA Research

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Ashutosh Kumar is a classically trained materials engineer. Having grown up with a passion for making things, he has explored steel design and studied stress fractures in alloys.

Throughout Kumar’s education, however, he was also drawn to biology and medicine. When he was accepted into an undergraduate metallurgical engineering and materials science program at Indian Institute of Technology (IIT) Bombay, the native of Jamshedpur was very excited — and “a little dissatisfied, since I couldn’t do biology anymore.”

Now a PhD candidate and a MathWorks Fellow in MIT’s Department of Materials Science and Engineering, and a researcher for the Koch Institute, Kumar can merge his wide-ranging interests. He studies the effect of certain bacteria that have been observed encouraging the spread of ovarian cancer and possibly reducing the effectiveness of chemotherapy and immunotherapy.

“Some microbes have an affinity toward infecting ovarian cancer cells, which can lead to changes in the cellular structure and reprogramming cells to survive in stressful conditions,” Kumar says. “This means that cells can migrate to different sites and may have a mechanism to develop chemoresistance. This opens an avenue to develop therapies to see if we can start to undo some of these changes.”

Kumar’s research combines microbiology, bioengineering, artificial intelligence, big data, and materials science. Using microbiome sequencing and AI, he aims to define microbiome changes that may correlate with poor patient outcomes. Ultimately, his goal is to engineer bacteriophage viruses to reprogram bacteria to work therapeutically.

Kumar started inching toward work in the health sciences just months into earning his bachelor's degree at IIT Bombay.

“I realized engineering is so flexible that its applications extend to any field,” he says, adding that he started working with biomaterials “to respect both my degree program and my interests."

“I loved it so much that I decided to go to graduate school,” he adds.

Starting his PhD program at MIT, he says, “was a fantastic opportunity to switch gears and work on more interdisciplinary or ‘MIT-type’ work.”

Kumar says he and Angela Belcher, the James Mason Crafts Professor of biological engineering, materials science and of the Koch Institute of Integrative Cancer Research, began discussing the impact of the microbiome on ovarian cancer when he first arrived at MIT.

“I shared my enthusiasm about human health and biology, and we started brainstorming,” he says. “We realized that there’s an unmet need to understand a lot of gynecological cancers. Ovarian cancer is an aggressive cancer, which is usually diagnosed when it’s too late and has already spread.”

In 2022, Kumar was awarded a MathWorks Fellowship. The fellowships are awarded to School of Engineering graduate students, preferably those who use MATLAB or Simulink — which were developed by the mathematical computer software company MathWorks — in their research. The philanthropic support fueled Kumar’s full transition into health science research.

“The work we are doing now was initially not funded by traditional sources, and the MathWorks Fellowship gave us the flexibility to pursue this field,” Kumar says. “It provided me with opportunities to learn new skills and ask questions about this topic. MathWorks gave me a chance to explore my interests and helped me navigate from being a steel engineer to a cancer scientist.”

Kumar’s work on the relationship between bacteria and ovarian cancer started with studying which bacteria are incorporated into tumors in mouse models.

“We started looking closely at changes in cell structure and how those changes impact cancer progression,” he says, adding that MATLAB image processing helps him and his collaborators track tumor metastasis.

The research team also uses RNA sequencing and MATLAB algorithms to construct a taxonomy of the bacteria.

“Once we have identified the microbiome composition,” Kumar says, “we want to see how the microbiome changes as cancer progresses and identify changes in, let’s say, patients who develop chemoresistance.”

He says recent findings that ovarian cancer may originate in the fallopian tubes are promising because detecting cancer-related biomarkers or lesions before cancer spreads to the ovaries could lead to better prognoses.

As he pursues his research, Kumar says he is extremely thankful to Belcher “for believing in me to work on this project.

“She trusted me and my passion for making an impact on human health — even though I come from a materials engineering background — and supported me throughout. It was her passion to take on new challenges that made it possible for me to work on this idea. She has been an amazing mentor and motivated me to continue moving forward.”

For her part, Belcher is equally enthralled.

“It has been amazing to work with Ashutosh on this ovarian cancer microbiome project," she says. "He has been so passionate and dedicated to looking for less-conventional approaches to solve this debilitating disease. His innovations around looking for very early changes in the microenvironment of this disease could be critical in interception and prevention of ovarian cancer. We started this project with very little preliminary data, so his MathWorks fellowship was critical in the initiation of the project.”

Kumar, who has been very active in student government and community-building activities, believes it is very important for students to feel included and at home at their institutions so they can develop in ways outside of academics. He says that his own involvement helps him take time off from work.

“Science can never stop, and there will always be something to do,” he says, explaining that he deliberately schedules time off and that social engagement helps him to experience downtime. “Engaging with community members through events on campus or at the dorm helps set a mental boundary with work.”

Regarding his unusual route through materials science to cancer research, Kumar regards it as something that occurred organically.

“I have observed that life is very dynamic,” he says. “What we think we might do versus what we end up doing is never consistent. Five years back, I had no idea I would be at MIT working with such excellent scientific mentors around me.”

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TILT Biotherapeutics Presents Clinical Data on TILT-123 in Ovarian Cancer at ASCO 2024

Published: May 28, 2024

Results reinforce potential to develop TILT-123 as a systemic therapy

HELSINKI, Finland, May 28, 2024 (GLOBE NEWSWIRE) -- TILT Biotherapeutics (TILT), a clinical-stage biotechnology company developing cancer immunotherapies, announces that it will present two abstracts at the American Society of Clinical Oncology (ASCO) Annual Meeting 2024. Abstract (5562) demonstrates promising safety and efficacy data of TILT-123 in ovarian cancer patients, whilst abstract (2658) demonstrates the potential for TILT-123 as an intravenous therapy.

Abstract (5562)* covers the results of a Phase I clinical trial of TILT-123 in combination with MSD’s (Merck & Co., Inc., Rahway, NJ, USA) anti-PD-1 therapy KEYTRUDA® (pembrolizumab), for the treatment of platinum-resistant or -refractory ovarian cancer, demonstrating the combination is safe and appears to induce disease control in a difficult-to-treat patient population. 14 patients (out of 15 enrolled) were evaluable for treatment response, with disease control achieved in 64.3%. Analysis of biological samples indicated the presence of TILT-123 and induction of T cells in injected and non-injected lesions. Long term survival was seen in some patients: Median progression free survival (PFS) and overall survival (OS) in all patients were 105 and 280 days. In patients with stable disease (SD) on day 92 by RECIST 1.1, median PFS was 174 days and median OS was 293 days.

Abstract (2658) introduces the development of oncolytic adenovirus TILT-123 as an intravenous (IV) therapy. Results across three Phase I trials showed that IV delivery results in systemic tumor transduction and accumulation of lymphocytes at tumors. This means TILT-123 reached tumors, despite not being directly injected into them, and successfully triggered an immune system toward the cancer. The IV injection of TILT-123 results in persistence of the virus in peripheral blood for up to 7 days. Tumor transduction was observed in 75% of patients in three Phase I trials on day 8 post TILT-123 systemic administration.

TILT Biotherapeutics’ founder and CEO, Akseli Hemminki, a cancer clinician who has personally treated hundreds of cancer patients with oncolytic viruses, said “This data presented at ASCO 2024 provides additional validation as we move forward in our clinical trials for patients with resistant or refractory ovarian cancer that have few other treatment options.”

TILT-123, an oncolytic adenovirus armed with tumor necrosis factor alpha (TNFα) and interleukin-2 (IL-2), is designed to enhance the efficacy of T-cell therapies, including immune checkpoint blockade or adoptive cell transfer. TILT’s approach uses oncolytic viruses to selectively replicate in and lyse cancer cells, while simultaneously stimulating immune responses towards the tumor.

References:

• Abstract (5562) : Poster #433 presented 3 June at 09:00-12:00
• Abstract (2658) : Poster #137 presented 1 June at 09:00-12:00

*The work was supported by the Assistant Secretary of Defense for Health Affairs endorsed by the Department of Defense, in the amount of $2,098,194.00, through the Ovarian Cancer Research Program under Award No. HT9425-23-1-0988. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Assistant Secretary of Defense for Health Affairs or the Department of Defense.

KEYTRUDA® is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Notes to Editors

About TILT Biotherapeutics

TILT Biotherapeutics is a clinical-stage biotechnology company developing cancer therapeutics based on its proprietary oncolytic adenoviruses armed with molecules including cytokines that can activate T cells and destroy cancer cells.

The company’s patented TILT® technology can be delivered intravenously, locoregionally, or intratumorally. It modifies the tumor microenvironment and has a broader systemic effect. By making cold tumors hot, it eliminates cancer’s ability to evade immune responses, thereby enhancing T-cell therapies such as immune checkpoint inhibitors, tumor infiltrating lymphocyte (TIL) therapy, and CAR T therapies.

TILT’s lead asset, TILT-123 also known as Igrelimogene litadenorepvec , is a 5/3 chimeric serotype adenovirus armed with two human cytokines: TNF alpha and IL-2. About fifty patients have been treated in four international trials sponsored by the company with promising initial efficacy responses observed in some of the patients.

The company’s pioneering approach has been recognized by industry leaders. It has two collaborations with MSD (Merck & Co., Inc., Rahway, NJ, USA) investigating TILT-123 in combination with KEYTRUDA® (pembrolizumab) in ovarian cancer (NCT05271318) and in refractory non-small cell lung cancer (NCT06125197). The company is also collaborating with Merck KGaA, Darmstadt, Germany, and investigating TILT-123 in combination with avelumab.

Based in Helsinki, Finland, and with an office in Boston, the company was established over a decade ago as a spin-out from the University of Helsinki. It has funding from Lifeline Ventures, Finnish Industry Investment (TESI), angel investors, Business Finland, the European Innovation Council, and the U.S. Department of Defense.

Media contacts

TILT Biotherapeutics

COO Aino Kalervo

[email protected]

Scius Communications

Katja Stout

+447789435990

[email protected]

Daniel Gooch

+447747875479

[email protected]

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May 28, 2024

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The importance of integrated therapies on cancer: Silibinin, an old and new molecule

by Impact Journals LLC

A new review paper titled "The importance of integrated therapies on cancer: Silibinin, an old and new molecule" has been published in Oncotarget .

In this new review, researchers Elisa Roca, Giuseppe Colloca, Fiorella Lombardo, Andrea Bellieni, Alessandra Cucinella, Giorgio Madonia, Licia Martinelli, Maria Elisa Damiani, Ilaria Zampieri, and Antonio Santo from Perderzoli Hospital and Fondazione Policlinico Universitario "A. Gemelli" begin their abstract by noting that the efficacy of coadjuvant molecules, in the landscape of cancer treatments, remains a focus of attention for clinical research with the aim of reducing toxicity and achieving better outcomes.

The researchers state, "Most of the pathogenetic processes causing tumor development, neoplastic progression, aging, and increased toxicity involve inflammation."

Inflammatory mechanisms can progress through a variety of molecular patterns. As is well known, the aging process is determined by pathological pathways very similar and often parallel to those that cause cancer development. Among these complex mechanisms, inflammation is currently much studied and is often referred to in the geriatric field as "inflammaging." In this context, treatments active in the management of inflammatory mechanisms could play a role as adjuvants to standard therapies.

Among these emerging molecules, silibinin has demonstrated its anti-inflammatory properties in different neoplastic types, also in combination with chemotherapeutic agents. Moreover, this molecule could represent a breakthrough in the management of age-related processes. Thus, silibinin could be a valuable adjuvant to reduce drug-related toxicity and increase therapeutic potential.

"For this reason, the main aim of this review is to collect and analyze data presented in the literature on the use of Silibinin, to better understand the mechanisms of the functioning of this molecule and its possible therapeutic role," the researchers explain.

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