Replication-Driven Vulnerabilities in Cyclin E-Overexpressing Ovarian Cancers
Abstract
Hypothesis and Rationale: A major subset of highly deadly ovarian cancers is associated with an increase in the amount of a protein called cyclin E1. Ovarian cancer patients with a high abundance of cyclin E1 show poor overall survival and have no curative treatment options. Therefore, there is a critical clinical need for new therapies to treat these ovarian cancers. We are developing ways to specifically target cyclin E1-high ovarian cancer cells, while leaving normal cells unaffected. DNA replication is important for cell survival. Our results suggest that, unlike normal cells, cancer cells with more cyclin E1 protein face multiple problems during DNA replication. These observations suggest that cancers with high cyclin E1 expression should be more dependent on repair pathways that allow them to fix problems during DNA replication. Therefore, inhibiting these pathways will selectively kill cyclin E1-high cancer cells. In this grant, we will identify (1) how cyclin E-high cancers deal with problems in DNA replication and manage to survive and (2) why cyclin E1-high cancers do not respond to chemotherapies. These efforts will help address key knowledge gaps on the etiology and chemotherapeutic response of CyclinE1-high ovarian cancers. Principal Investigator’s (PI) Career Goal in Ovarian Cancer: As an independent investigator, I am committed to leveraging my postdoctoral training at the interface of DNA repair biology and BRCA-mutant ovarian cancers to expand the scope of my research to other ovarian cancers subtypes that are highly lethal and have no defined cure. I therefore chose to study cyclin E1-high ovarian cancers. DNA damage has an integral role in the etiology of this ovarian cancer, and hence my training and expertise position me well to pursue the proposed research question. To catalyze my efforts in developing clinically meaningful research, I chose my mentor to be Dr. Dineo Khabele, who has extensive translation and clinical research experience with cyclin E1-high gynecological malignancy. Furthermore, I aim to position myself at the forefront of ovarian cancer research by (1) attending conferences that link DNA repair to cancer etiology and therapy, (2) attending workshops on the use of cutting-edge tools to study ovarian cancers, (3) developing fruitful collaborations with researcher having complementary expertise (e.g., in vivo mouse modeling, medical geneticist), and (4) actively engaging with the OCA community. PI’s participation in and contribution to the growth of the OCA. I strongly believe that a highly collaborative environment that enables the exchange of expertise and resources creates the strongest foundation for breakthrough discoveries. By actively participating in the monthly webinars and annual workshops organized by OCA, I will engage with leaders and peers in the field of ovarian cancer where our complementary expertise can catalyze seminal discoveries for the prevention, diagnosis, and cure of this deadly disease. I also look forward to contributing to the review of grant applications and engaging with patient advocates, with the ultimate goal of supporting the OCRP mission toward developing innovative platforms to combat ovarian cancer. Ultimate Applicability of the Research: Type of Patients. Ovarian cancer patients with amplification or copy number gain in gene CCNE1, which encodes for cyclin E1 protein. This includes 20-30% of all cases with high- grade serous ovarian carcinoma, the most deadly and common ovarian cancer. Potential clinical applications, benefits, and risks. Applications and Benefits: 1. Identification of new therapeutic targets that selectively kill ovarian cancer cells without harming normal healthy cells. 2. Approaches to mitigate cancer progression. 3. Development of a biomarker platform to predict responses to therapy. Risks: Our initial studies are based on patient-derived cell line models of ovarian ca
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310133
Entities
People
- Priyanka Verma
Organizations
- United States Army
- Washington University in St. Louis