The purpose of this study is to develop a comprehensive mathematical model of DNA double-strand break (DSB) repair in a cell cycle-dependent manner to analyze the improved radiosensitivity of prostate cancer (PCa) cells to ionizing radiation (IR) when radiation treatment is combined with androgen deprivation therapy (ADT). The effectiveness of the combination treatment, which is currently a standard treatment for PCa, depend on DSB repair capacity of the cells as these are the main lesions following IR. It is reported in the literature that the major DSB repair pathways, non-homologous end joining (NHEJ) and homologous recombination (HR), are both impaired after ADT, which then resulted in increased radiosensitivity and better IR treatment outcomes in PCa. In our previous work, we have developed quantitative models for NHEJ and HR individually to analyze the mechanism of the effect of ADT on IR treatment outcomes through impaired repair dynamics. The present work combines these two models in a cell cycle-dependent manner in order to develop a comprehensive model to analyze the repair dynamics after IR only and IR+ADT treatments. NHEJ is the major pathway, whereas HR is restricted to S- or G2-phases of the cell cycle after DNA replication has been completed and we have incorporated the cell cycle dependent contributions of the NHEJ and HR models in our comprehensive model. The literature data used in the development of these previous models were from both in vitro experiments as well as clinical data from PCa patients. In our comprehensive model, we have used the data from the literature to determine the distribution of the initial DSBs for cells in different cell cycle phases as the damage depends on the cell cycle phase at the time of radiation. We have incorporated the data on the percent contributions of NHEJ and HR repair in different cell cycle phases into the model and calculated the repair outcomes from NHEJ and HR models according to these ratios. Cell cycle arrest is implemented in relation to the amount of remaining DSBs in each cell cycle phase after repair. Using the number of unrepaired DSBs, we have calculated the proportion of cells that would progress to the next cell cycle phase as well as the proportion for which the cell death mechanism is triggered. The simulation results showed that ADT combined with IR has enhanced the treatment outcome. The cell survival rate was lower for the combination treatment case (55.7% compared to 62.1 % of IR only case). The cell proliferation was also significantly slower (85-95h doubling time compared to 35-45h of IR only case). The results agreed well with the experimental data that showed 30h and 95.5 h of doubling times for IR only and IR+ADT treatment respectively. The comprehensive model outcomes show that impaired NHEJ and HR dynamics as a result of ADT have the potential to enhance the IR treatment outcomes for PCa patients. Citation Format: Mengdi Qian, Alexandru Almasan, Evren Gurkan-Cavusoglu. Cell cycle-dependent, comprehensive mathematical modeling of the role of DNA repair in response to radiotherapy for prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5499.

In this study, we quantitatively analyze the mechanism by which androgen deprivation therapy (ADT) is enhancing radiosensitivity in prostate cancer (PCa) patients. It has been shown in laboratory experiments, as well as in patient data in the literature, that the androgen receptor (AR) reduces the effectiveness of ionizing radiation treatment by enhancing the non-homologous end joining (NHEJ) repair of radiation damage. The suppression of AR by ADT suppresses the activity of NHEJ that leads to radiosensitivity in PCa patients. In this paper, we have studied this positive interaction between AR and NHEJ using mathematical models of the NHEJ that we have developed using both the experimental and clinical data for PCa. Our results show that the biological observation of suppression of AR by ADT leading to down-regulation of the first NHEJ protein Ku and NHEJ is a plausible biological mechanism that explains both the experimental and clinical observations in the literature. The presented analysis is the first step in quantitatively analyzing possible treatment scenarios to find the optimal treatment strategies for PCa using the combination treatment with ADT, NHEJ inhibitors, and IR.

The purpose of this study is to computationally analyze the effect of inhibition of base excision repair (BER) in the response of cancer cells to treatment with 5-fluorodeoxyuridine. 5-fluorouracil (5-FU) and its metabolite 5-fluorodeoxyuridine (5-FdU) are standard treatments for different solid tumors and especially for colon cancer. In the literature, it is shown that the depletion of uracil DNA glycosylase (UDG), one of the enzymes that initiate the BER pathway, enhanced the cytotoxicity of 5-FdU, making UDG a potential target to enhance efficacy of chemotherapeutic agents. It is also shown that the activity of UDG is significantly higher in colon cancer cells compared to normal tissue. We have developed a computational model of the BER pathway to capture the BER dynamics in colon cancer cell lines after treatment with 5-FdU. Our model is composed of a series of ordinary differential equations where the parameters are the kinetic rate constants and the enzyme concentrations. We have used the data from the literature to initially parameterize our models. We have then used least square estimation to find the parameters that will capture the BER time course for colon cancer cells after 5-FU treatment using the experimental data from the literature. We have performed sensitivity and identifiability analyses to determine the parameters that are reliably estimated. The experimental data from the literature showed that the depletion of UDG resulted in incorporation of uracil and 5-FU in the DNA. We have computationally replicated this effect by decreasing the protein concentration of UDG in the models and simulating the amount of remaining 5-FU in the DNA after BER with reduced activity has taken place. We have studied the depletion effect for different protein concentrations of UDG and the results have shown that the accumulation of 5-FU in these colon cancer cells correlate with the level of UDG. The suppression of UDG activity has the potential to enhance the outcome of treatment with 5FdU, and we will use the developed computational models to quantitatively optimize these effects in our future work. Citation Format: Mengdi Qian, Alexandru Almasan, Evren Gürkan-Çavusoglu. Computational models of the role of base excision repair in sensitization of cancer cells to 5-fluorodeoxyuridine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4265.

No 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