Abstract 2707: Quantitative analysis of the role of androgen receptor in radiation treatment for prostate cancer

The purpose of this study is to quantitatively investigate the mechanism of androgen receptor (AR) and non-homologous end joining (NHEJ) interaction after and ionizing radiation (IR) and androgen deprivation therapy (ADT) treatment. In most clinical treatment approaches, a combination of ADT and IR is used in order to improve prostate patients’ overall survival probability. It is found that AR interacts with NHEJ pathway, a major double strand break (DSB) repair pathway. We have developed a mathematical model of the NHEJ pathway that is composed of a series of ordinary differential equations. The kinetic rate constants constitute the unknown parameters of the model and we have estimated these parameters using least square estimation. 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 prostate cancer patients. Both sets of data demonstrated the effects of AR on DSB repair by NHEJ. The in vitro data suggest that AR enhances DSB repair by inducing expression/activity of DNA-PKcs, which is a key protein in NHEJ. The clinical data show that the effect is through the first NHEJ protein complex that is recruited to DSB, Ku70/80. We have developed the models for IR treatment alone or in combination with ADT to determine which of these mechanisms can explain the behavior in both data sets simultaneously. 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. We have shown that when the rate constant for the initiation protein Ku70/80 is decreased to half in the IR+ADT case compared to the IR only case, the model outputs captured the observations in both experimental and clinical data. The rate constant for Ku70/80 is proved to be both sensitive and identifiable, indicating that the two-fold difference in the rate constants of IR only and IR+ADT cases is biologically relevant. Therefore, we conclude that when ADT is applied, AR significantly slows down the kinetic activity of Ku70/80, thus the DSB repair by NHEJ. The suppression of AR activity through ADT has the potential to enhance the IR treatment outcomes for the prostate cancer patients that are resistant to IR-only treatment. Citation Format: Mengdi Qian, Alexandru Almasan, Evren Gurkan-Cavusoglu. Quantitative analysis of the role of androgen receptor in radiation treatment for prostate cance