Abstract 4533: In silico analysis of enhanced radiosensitivity in radiation treatment combined with androgen deprivation therapy for prostate cancer

Abstract

Abstract The purpose of this study is to quantitatively analyze the improved radiosensitivity of prostate cancer cells to ionizing radiation (IR) when radiation treatment is combined with androgen deprivation therapy (ADT). The double strand breaks (DSBs) induced by ionizing radiation are repaired primarily by non-homologous end joining (NHEJ). It is reported in the literature that NHEJ is impaired after ADT, which then results in increased radiosensitivity and better IR treatment outcomes in prostate cancer. In this study, we have used our models for NHEJ repair of DSBs under IR treatment and IR + ADT combination treatment conditions to determine how the combination treatment results in better outcomes. We have modeled the effect of multiple doses of IR that are delivered 24 hours apart to mimic the conventional, fractionated radiation treatment. The analysis results showed that the DSBs accumulate more in the case of combined treatment with ADT compared to faster and more efficient repair when only IR is applied. We have used the experimental data on relative cell numbers and relative sub-G1 cell numbers from the literature to determine the difference in the levels of DSBs that lead to cell death differences between the two treatment strategies. The literature data also shows that there is patient response variability to ADT in terms of the reduction in the levels of Ku70/80, which is the first NHEJ protein complex that is recruited to DSBs. We have modeled this patient variability in our models by introducing variability to Ku70/80 protein concentrations used in the simulations. Our simulation results agree with the observation from clinical data that lower concentration levels of Ku70/80 lead to better radiosensitization. The amount of IR can be adjusted with respect to the level of radiosensitization after ADT on a patient specific level to achieve a desired level of DSBs that will lead to maximum cell death; this dose optimization effort will be the next step in our quantitative analysis. Citation Format: Mengdi Qian, Alexandru Almasan, Evren Gürkan-Çavusoglu. In silico analysis of enhanced radiosensitivity in radiation treatment combined with androgen deprivation therapy for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4533. doi:10.1158/1538-7445.AM2017-4533