Posted September 30, 2020

Rugang Zhang, Ph.D., The Wistar Institute
William Foulkes, MBBS, Ph.D., FRCPC, Jewish General Hospital
Sidong Huang, Ph.D., McGill University
David Wilson, M.D., Ph.D., Washington University

There are more than 30 different types of ovarian cancer. Each is classified by the type of cell from which they originate: epithelial cells, which make up the outer layer of the ovary and line the fallopian tubes; germ cells, which form eggs; or stromal cells, which produce and release hormones. The most common ovarian cancers are epithelial high-grade serous carcinomas, which account for 68% of ovarian cancer and have the most ovarian cancer-associated mortalities. Much research goes into their understanding and treatment. While the other types of ovarian cancers are rare and often less aggressive, these ovarian cancer patients would still significantly benefit from a treatment plan that is tailored to their needs and specific diagnosis. The Ovarian Cancer Research Program (OCRP) supports research in these rare ovarian cancers, and this research has led to the discovery of promising therapeutics for these patients. 

Clear cell and endometrioid carcinomas 

Ovarian clear cell carcinoma (OCCC) makes up about 5 percent of all ovarian cancer and carries the worst prognosis of all ovarian cancer epithelial subtypes when diagnosed at an advanced stage. Endometrioid carcinomas are a subtype of epithelial ovarian cancer that are often the result of a disease in the reproductive system, such as endometriosis. About 13 percent of all ovarian tumors are endometrioid tumors. The gene ARID1A (AT-rich interactive domain-containing protein 1A), is the highest mutated gene in OCCC and occurs in over 50% of the cases. In addition, ARID1A is also mutated in about 30% of endometrioid carcinomas. With support from a Fiscal Year 2015 (FY15) OCRP Investigator-Initiated Research Award (IIRA), Dr. Rugang Zhang began developing an effective targeted therapeutic for ARID1A-mutated ovarian cancers. 

Dr. Zhang and his team determined that ARID1A is a repressor of the genes encoding histone deacetylase 6 (HDAC6) and programmed death-ligand 1 (PD-L1). They demonstrated that ARID1A-mutated ovarian cancer cells are selectively sensitive to the inhibition of HDAC6. They also found that HDAC6 inhibition synergizes with an anti-PD-L1 therapy in ARID1A mutated ovarian cancer and reduced tumor burden and improved survival in mice bearing ARID1A-inactivated OCCCs. This suggests a combination of HDAC6 inhibition and anti-PD-L1 therapy as an effective treatment strategy for ARID1A-mutant tumors. The HDAC6 inhibitor ACY1215 is now in clinical development for other cancer types, and the immune checkpoint blockade anti-PD-L1 therapy is Food and Drug Administration (FDA)-approved. Dr. Zhang has been awarded an FY19 OCRP IIRA to continue this research, developing therapeutic strategies for ARID1A-mutated OCCC and endometrioid ovarian cancers using clinically available applicable agents. 

Ovarian small cell carcinoma 

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare and often lethal cancer of young women. Fewer than 500 cases have been reported in the medical literature to date. The origin is not clear, it has been suggested that SCCOHT might be a type of germ cell tumor. In 2014, multiple groups, including Dr. William Foulkes’ group, discovered that SCCOHT is caused by mutations in the chromatin remodeler gene, SMARCA4, which leads to loss of SMARCA4 protein expression. SMARCA4 loss is not directly targetable, but with OCRP support from a FY14 IIRA, Dr. Foulkes and co-Principal Investigator on this proposal, McGill University functional genetics expert Dr. Sidong Huang, set out to evaluate the SMARCA4 pathway to identify druggable target genes dysregulated in SCCOHT. Drs. Foulkes and Huang uncovered a cyclin-dependent kinase 4/6 (CDK4/6) vulnerability due to cyclin D1 deficiency in SCCOHT cells that is caused by SMARCA4 loss. The team demonstrated that CDK4/6 inhibitors were effective in inhibiting the growth of SCCOHT tumors in mouse models. CDK4/6 inhibitors have been approved by the FDA for treating breast cancers. Drs. Foulkes and Huang identified CDK4/6 as a druggable vulnerability of SCCOHT, providing a rationale for a clinical trial using the approved CDK4/6 inhibitors to treat this often fatal ovarian cancer of young women. 

Ovarian granulosa cell tumors 

Adult-type granulosa cell tumors (AGCTs) are sex cord stromal tumors and represent 3% to 5% of ovarian malignancies. The 5-year survival is >90% for patients with stage I AGCT, but is significantly worse for patients with higher stage or recurrent disease. The favorable 5-year survival for individuals with low-stage AGCT tends to mask the critical problem of late relapse, which many women with stage I AGCT suffer 6-8 years after the initial diagnosis. Given the high rate of late relapses, more effective follow-up therapies are needed. An OCRP FY15 Pilot Award supported Dr. David Wilson’s research exploring whether patients with AGCT could benefit from hormonal therapy. Dr. Wilson’s team used a multimodal approach that combined next-generation sequencing, quantitative real-time PCR, RNA in situ hybridization, and immunohistochemistry to profile the expression of a number of hormone receptors in a large cohort of AGCTs with rich clinical and follow-up data. Their results indicate a specific pattern of hormonal dependency in AGCTs and support the further clinical exploration of hormonal modulators in the treatment of AGCT. 

This research highlights the growing understanding that the best treatment options for patients are likely specific to the genomic and molecular aberrations that each ovarian cancer subtype display. By funding research specific to each ovarian cancer subtype, the OCRP hopes to enable effective treatment options for women affected by all ovarian cancer. 

Publications:

Tischkowitz M, Huang S, Banerjee S, et al. 2020. Small-cell carcinoma of the ovary, hypercalcemic type–genetics, new treatment targets, and current management guidelines. Clin Cancer Res. DOI: 10.1158/1078-0432.CCR-19-3797. 

Xue Y, Meehan B, Macdonald E, et al. 2019. CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary. Nat Commun 10(1):558. doi:10.1038/s41467-018-06958-06959. 

Haltia UM, Pihlajoki M, Andersson N, et al. 2020. Functional profiling of FSH and Estradiol in ovarian granulosa cell tumors. J Endocr Soc 4(4):bvaa034. doi:10.1210/jendso/bvaa034.

Bitler BG, Wu S, Park PH, et al. ARID1A-mutated ovarian cancers depend on HDAC6 activity. Nat Cell Biol 19(8):962-973. doi:10.1038/ncb3582. 

Fukumoto T, Fatkhutdinov N, Zundell JA, et al. HDAC6 inhibition synergizes with anti-PD-L1 therapy in ARID1A-inactivated ovarian cancer. Cancer Res 79(21):5482-5489. doi:10.1158/0008-5472.CAN-19-1302 

Links:

Public and Technical Abstracts: Synthetic Lethal Therapeutic Approaches for ARID1A-Mutated Ovarian Cancer

Public and Technical Abstracts: Systematic Approaches to Dissect Driver Pathways in Small Cell Carcinoma of the Ovary, Hypercalcemic Type 

Public and Technical Abstracts: Ovarian Granulosa Cell Tumor: New Insights into the Clinical Challenge of Late Relapse

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