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System Biology Analysis of the Role of DNA Repair in Cancer Treatment Outcome

Qian, Mengdi
http://rave.ohiolink.edu/etdc/view?acc_num=case1560212679611413

Abstract Details

, Doctor of Philosophy, Case Western Reserve University, EECS - System and Control Engineering.
Cancer is one of the most lethal and hard to cure diseases. The common treatments for cancer include surgery, radiation therapy, chemotherapy, immunotherapy and hormone therapy. Ionizing radiation (IR) is one of the main clinical treatments for cancer and it works by inducing DNA double strand breaks (DSBs), which are the most toxic DNA lesions that lead to cell death. The effectiveness of IR treatment depends on the amount of induced damage and the DNA damage repair status of the cancer cells. DSBs are repaired by multiple DNA repair pathways and this repair reduces the effectiveness of the treatment leading to resistance to IR. It has been shown in the literature that by targeting the DNA repair pathways the treatment efficacy can be modulated. In this work, a systems biology approach is used to quantitatively study the role of DNA repair pathways in determining and improving the radiation treatment outcome. Specifically, the mathematical models of DNA repair pathways, non-homologous end joining (NHEJ) and homologous recombination (HR), are developed for analyzing the role of DNA repair in enhancing the treatment sensitivity for prostate cancer (PCa) when a combination of radiation and hormone deprivation therapies is used. DSBs are repaired by one of the two DNA repair pathways: NHEJ and homologous recombination (HR). NHEJ is the major pathway, whereas HR is restricted to S- or G2-phases of the cell cycle after DNA replication has been completed. The cell cycle specific contribution of the repair pathways are incorporated into the computational models. A comprehensive identifiability analysis is carried out to determine the factors affecting parameter identifiability and strategies to increase identifiability are developed. In parallel to the NHEJ and HR models, a computational model of the base excision repair (BER) pathway is developed to analyze its role in response to chemotherapy under different treatment scenarios. Combination treatment strategies that aim to inhibit the functional DNA repair pathways for the cancer cells that are defective in other repair pathways achieve synthetic lethality. One such strategy is the use of PARP inhibitors (PARPi) in addition to the combination treatment with IR and ADT. 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. The effect of using PARPi in this scenario has been computationally analyzed in this work by extending the modeling efforts to include the effect of PARP inhibitors on the treatment outcome. The inhibition of BER by PARPi is also quantitatively studied. The models and findings in this work can then be extended to other cancers, such as lung cancer and ovarian cancer that benefit from similar synthetic lethality.
Evren Gurkan Cavusoglu (Advisor)
Biology; Systems Design

Recommended Citations

Citations

  • Qian, M. (n.d.). System Biology Analysis of the Role of DNA Repair in Cancer Treatment Outcome [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1560212679611413

    APA Style (7th edition)

  • Qian, Mengdi. System Biology Analysis of the Role of DNA Repair in Cancer Treatment Outcome. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1560212679611413.

    MLA Style (8th edition)

  • Qian, Mengdi. "System Biology Analysis of the Role of DNA Repair in Cancer Treatment Outcome." Doctoral dissertation, Case Western Reserve University. Accessed MAY 04, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=case1560212679611413

    Chicago Manual of Style (17th edition)

case1560212679611413
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