Abstract 686: Quantitative analysis of the role of homologous recombination in response to radiotherapy for prostate cancer

Abstract

Abstract The purpose of this study is to computationally analyze how the interaction between androgen receptor (AR) and homologous recombination (HR) affects the treatment outcome for ionizing radiation (IR) combined with androgen deprivation therapy (ADT) for prostate cancer (PCa). Combination treatment with radiation and ADT is currently a standard treatment for PCa. The effectiveness of radiation treatment alone depends on the cells’ capacity to repair the damage that is mostly in the form of double-strand breaks (DSBs). Two major pathways that repair DSBs are non-homologous end joining (NHEJ) and HR. The experimental data in the literature show that AR promotes both NHEJ and HR following IR, and inhibition of AR by ADT impairs both of these pathways in PCa cells leading to either increased radiosensitivity or sensitization to PARP inhibitors. In our previous work, we developed mathematical models of the NHEJ pathway and in this current work we have developed such models for HR to comprehensively analyze the response of PCa cells to IR combined with ADT. We have modeled HR using a series of ordinary differential equations. The parameters that needed to be estimated are the kinetic rate constants, and we have used least square estimation to obtain these model parameters. The data sets used in the parameter estimation were obtained from the literature and they were from both in vitro experiments as well as clinical data from PCa patients. The experimental data show that AR influences the DNA end resection that is required for proficient HR and we have computationally included this effect in the kinetics of the models. We have developed models for IR treatment alone or in combination with ADT. We have carried out sensitivity analysis and identifiability tests on all the parameters from both models in order to determine the parameters that are reliably estimated. The outputs from both NHEJ and HR models show that the suppression of AR activity through ADT has the potential to enhance the IR treatment outcomes for PCa patients. The impairment of HR by ADT also opens up an avenue for achieving synthetic lethality using PARP inhibitors as shown in the literature; in the future we are planning to extend our modeling efforts to include the effect of PARP inhibitors on the treatment outcome. Citation Format: Mengdi Qian, Alexandru Almasan, Evren Gürkan-Çavusoglu. Quantitative analysis of the role of homologous recombination in response to radiotherapy for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 686.