Abstract 2182: The evolution of high grade serous ovarian cancer under the pressure of non-cytotoxic and cytotoxic treatment
Authors: Kabeer Farhia , Lam Goldman , Adam Naila , Douglas Maxwell , El-Naggar Amal , Kalantari Forouh , Han Mengke , Au Vinci , Van Vliet Michael , Shen Cindy , Beaty Sean , Lai Daniel , Mungall Andy , Moore Richard , Aparicio Sam , Roth Andrew , Huntsman David , Drew Yvette 
Published: April 2023

Abstract
Introduction: High-grade serous ovarian cancer (HGSOC) is driven by loss of TP53 and genome instability . Despite the recent success of PARP inhibitors, advanced BRCA mutant and homologous recombination repair deficient (HRD) HGSOC, chemotherapy remains the first line treatment. Little is known about how chemotherapy exposure alters tumor heterogeneity and subsequent response to targeted therapies. Certain mutations may survive the exposure of chemotherapy better than others. The question of whether targeted therapies should be given before or after response to chemotherapy also remains unanswered. We use the principles of natural selection to investigate how HGSOC evolves over time and selection operates on clones in the context of cytotoxic/non-cytotoxic combination therapies, and what changes in genomes/transcriptomes at the single cell level drive tumor progression.
Methods: Cell lines ID8 Trp53 −/−; Brca1 −/− and WT were used to represent defective/proficient homologous recombination were given intraperitoneally to C57B6 mice to develop HGSOC models. Transfected Luciferase expression in the cells used to monitor tumor response to olaparib (Ola)+/- Bevacizumab (BEV-various doses) +/- Atezolizumab (ATz) combinations by bioluminescence imaging (BLI). Ascitic fluid and mouse organs were harvested for the evidence of seeding and identification of biomarkers. In addition, 10 treatment naïve HGSOC PDX were developed in immunodeficient mice and treated with either cisplatin or olaparib. Single-cell whole-genome sequencing (scWGS) was performed using direct library preparation (DLP+). Hierarchical clustering and Sitka are used to identify the clonal structure of each condition following treatment. Phylogenetic tree was computed using copy number data.
Results: In the BRCA WT HRp study group, the greatest response was seen in the triplet Ola+BEV+ATz combinations and interestingly no significant differences were observed using a lower dose of BEV. Furthermore, from scWGS data of PDX passages we captured initial clonal heterogeneity leading to emergent clones. We found evolving copy number changes on chromosome 19, 8, 3 and loss of heterozygosity of TP53.
Conclusion: The triplet combination of low-dose-intensity bevacizumab with other non-cytotoxic drugs was an effective regimen for BRCA WT syngeneic mouse tumors. In HGSOC PDX, we are able to capture diversification between HGSOC PDX passages-specifically after drug exposures.
Citation Format: Farhia Kabeer, Goldman Lam, Naila Adam, Maxwell Douglas, Amal El-Naggar, Forouh Kalantari, Mengke Han, Vinci Au, Michael Van Vliet, Cindy Shen, Sean Beaty, Daniel Lai, Andy Mungall, Richard Moore, Sam Aparicio, Andrew Roth, David Huntsman, Yvette Drew. The evolution of high grade serous ovarian cancer under the pressure of non-cytotoxic and cytotoxic treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2182.