Evaluation of new treatments and biomarkers for ovarian carcinomas with CCNE1 amplification

• Grant number: 24/13952-4
• Support Opportunities: Regular Research Grants
• Start date: February 01, 2025
• End date: January 31, 2028
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Alexandre André Balieiro Anastácio da Costa
• Grantee: Alexandre André Balieiro Anastácio da Costa
• Host Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil
• Associated researchers: Cláudia Malheiros Coutinho Camillo ; Dirce Maria Carraro ; Giovana Tardin Torrezan ; Glauco Baiocchi Neto ; Louise de Brot Andrade ; Tiago Góss dos Santos

Abstract

Ovarian high-grade serous carcinoma (HGSC) is the most frequent histologic type of ovarian cancer. In the past 15 years, the discovery of PARP inhibitors has changed ovarian cancer treatment in different clinical settings.About 20% of HGSC present CCNE1 amplification (amp), a gene that encodes cyclin E1, a central regulator of cell cycle and DNA replication. Despite the relative success of new therapies for HGSC, CCNE1amp tumors are resistant to conventional treatment with platinum agents and PARP inhibitors and bear the worst prognosis among HGSC patients. Replication stress (RS) is the hallmark of CCNE1amp tumors. RS increases genome instability and makes CCNE1amp cells dependent on the homologous recombination (HR) pathway. Indeed, CCNE1amp and BRCA1/2 mutations are mutually exclusive. Recent approaches to treat CCNE1amp tumors focused on ATR, CHK1, WEE1, and PKMYT1 inhibitors that exploit replication stress and CDK2 inhibitors that target cyclin E1 leading partner. Despite the rationale and promise of preclinical activity, the response rates in early clinical trials were seldom higher than 30%, and progression-free survival is around six months. Antiangiogenic therapy is approved to treat HGSC in different clinical scenarios. Since antiangiogenic therapy induces context-dependent homologous recombination deficiency, we hypothesized that cyclin E1 overexpressing tumors would be more sensitive to antiangiogenic drugs. Indeed, our group showed in a retrospective cohort study that patients whose tumors overexpress cyclin E1 derived the most significant benefit of antiangiogenic therapy. After our study, the MD Anderson phase I group confirmed our results in another retrospective study, which showed that patients with CCNE1amp tumors had better outcomes in trials including any antiangiogenic therapy. We now hypothesize that the combination of antiangiogenic therapy may improve the efficacy of ATR/CHK1/WEE1 inhibitors and a CDK2 inhibitor, which are currently in early-phase clinical development. The main aim of this project is to test whether adding antiangiogenic therapy to ATR/CHK1/WEE1 inhibitors and a CDK2 inhibitor increases its efficiency compared to monotherapy in a set of preclinical ovarian cancer models with CCNE1amp. Our specific aims are (1) Generating a biorepository of patient-derived ovarian cancer explants in the form of patient-derived ovarian cancer xenografts (PDX), associated with a patient cell culture platform in the form of organoids (PDOs). (2) Testing the efficacy of the combination of ATR/CHK1/WEE1 inhibitors with bevacizumab and CDK2 inhibitors with bevacizumab in PDX of ovarian cancer with and without CCNE1amp. (3) Testing the lethality of ATR/CHK1/WEE1 inhibitors and CDK2 inhibitors as monotherapy in ovarian cancer PDOs with and without CCNE1amp, and evaluate the impact of hypoxia on the effectiveness of these treatments. (4) Testing the lethality of ATR/CHK1/WEE1 inhibitors and CDK2 inhibitors as monotherapy in ovarian cancer cell lines with and without CCNE1amp, and evaluate the impact of hypoxia on the effectiveness of these treatments. (5) Explore the mechanisms of action of ATR/CHK1/WEE1 inhibitors and CDK2 inhibitors in ovarian cancer cell lines and ovarian cancer PDOs and the potential mechanisms of synergism with hypoxia. (6) Evaluating the impact of antiangiogenic therapy with bevacizumab in patients with tumors with cyclin E1 overexpression compared to tumors without cyclin E1 overexpression in a retrospective cohort of patients with ovarian cancer.If our hypothesis is confirmed we will show the improvement in treatment efficacy of the new agents targeting CCNE1amp tumors with the addition of antiangiogenic therapy. It will be valuable preclinical data to set the stage for a phase 1 trial testing combinations of these agents with an antiangiogenic agent in a biomarker-selected population. (AU)