Targeted Therapeutic Opportunities for Ovarian Clear Cell, Small Cell, and Endometrioid Carcinomas
Abstract
Ovarian cancer is one of the most lethal gynecological malignancy in the United States. Currently, at least 85% of ovarian cancer patients do not have viable targeted therapy options. Some of these patients are subject to highly aggressive ovarian cancer subtypes, including clear cell, small cell, and endometrioid carcinomas. These carcinomas can be characterized in part by damage to tumor suppressor genes ARID1A or related members of the SWI/SNF chromatin remodeling complex, which results in dysregulation and promotion of oncogenesis. Mutations in these genes may also present tumor vulnerabilities that can be exploited by the development of new therapeutic strategies. The central problem our proposal addresses is the development of novel therapeutic strategies to treat ovarian cancer patients who are in critical need of a targeted therapeutic strategy to mitigate disease burden. Here, we will explore an exciting small molecule therapeutic approach, termed a degrader, for their ability to exploit specific biomarkers as tumor vulnerabilities to provide a targeted therapeutic strategy for ovarian clear cell, small cell, and endometrioid carcinomas. Degraders act by controlled removal of a desired protein target, many of which are typically otherwise considered undruggable by more traditional inhibition mechanisms. Degradation of a protein can have stronger biological outcomes than more traditional inhibition of the protein, as removal of the protein is often catalytic and the degradation event is irreversible. We have developed a class of dual degraders that target two proteins: casein kinase 1 alpha (CK1?) and IKZF2. Degradation of these therapeutic targets can promote selective and desirable apoptosis and differentiation in cancer cells. Our prior efforts have shown that these compounds work well to mitigate a form of blood cancer, acute myeloid leukemia. In the course of our studies, we found that ovarian cancer cell lineages are also particularly sensitive to our therapeutic targets and that sensitivity in these cell lines correlated strongly with the presence of a damaging mutation to ARID1A. We therefore hypothesized that ovarian cancer lineages with damaging mutations to tumor suppressor genes like ARID1A or the related SWI/SNF chromatin remodeling complex would be particularly sensitive to a targeted therapeutic strategy that promotes apoptosis and differentiation. We will test this hypothesis by systematically establishing a connection between the mechanism of action of our small molecule degraders in promoting apoptosis to damaging mutations in tumor suppressor genes in ovarian cancer. First, we will test specific ovarian cancer subtypes for sensitivity to our therapeutic strategy, followed by evaluation of CK1? and downstream apoptosis as a primary driver of that sensitivity. Second, we will use the existence of a damaging mutation to a tumor suppressor gene, like ARID1A, to predict the efficacy of our degraders and evaluate the mechanistic drivers that promote sensitivity in the best model systems. These studies will enable us to conclusively connect specific biomarkers to stratify patient populations who would respond to our therapeutic target in the long-term. Finally, we will undertake rigorous efforts to develop new small molecule degraders with superior biological and chemical properties in order to bring these compounds to the clinic. In sum, these aims will provide a critical connection between a biomarker of relatively untreatable ovarian cancer subtypes to a therapeutic target that is accessed through a small molecule degrader. The successful outcome of these studies will benefit ovarian cancer patients by providing them with new targeted therapy options that are currently not available for these patient populations. In the short term, we will identify a novel targeted therapeutic strategy for ovarian small cell, clear cell, and endometrioid carcinomas using models of these tumo
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310263
Entities
People
- Christina M. Woo
Organizations
- President and Fellows of Harvard College
- United States Army