Genome-wide Patterns of DNA Damage and Repair in Resistance to Platinum-Based Chemotherapy

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Project Summary/Abstract Platinum-based chemotherapies are a mainstay of solid tumor treatment. Their mechanism of action is to form DNA adducts which ultimately should result in cell death. Unfortunately, these drugs have serious side effects and rates of resistance are high; about 40% of colorectal tumors are platinum-resistant. Understanding the molecular mechanisms of resistance could help maximize efficacy by countering drug resistance. A number of studies claim that enhanced DNA damage repair is a mechanism of platinum-based chemotherapy resistance, but the evidence so far is incomplete and inconsistent. Additionally, it has been hypothesized that timing of platinum treatments based on circadian control of nucleotide excision repair will improve tumor response to platinum-based chemotherapies; however a more complete understanding of these interactions is necessary in order to optimize treatment plans. The overall purpose of this project is to determine the role of DNA damage repair and circadian rhythm in tumor response to platinum-based chemotherapy. To address this knowledge gap, the Sancar laboratory recently created methods which measure genome-wide adduct formation and damage repair at a single-nucleotide resolution. I hypothesize that there will be a difference in nucleotide excision repair activity between platinum-sensitive and platinum-resistant tumor models and at different circadian time points. These differences may clarify the role of repair and treatment timing in platinum response. Aim 1 will determine the role of nucleotide excision repair in tumor response to platinum-based chemotherapies by defining the amount and rate of repair, and the genome-wide repair patterns in platinum-resistant and platinum-sensitive colorectal cancer cell lines. The long-term impact of this aim is to provide a more complete understanding of the nucleotide excision repair response to platinum-based chemotherapies and to identify repair signatures to better understand treatment response. Aim 2 will explore the impact of circadian rhythm on platinum-induced damage repair patterns in both platinum -sensitive and -resistant patient derived xenografts. Nucleotide excision repair is controlled by the circadian clock; thus exploring the influence of treatment timing on repair, and how this impact may differ between platinum -sensitive and -resistant models, is essential for a complete understanding of patients’ responses to platinum-based treatment. The long-term goal is to determine the optimal timing of treatment to maximize the therapeutic index. Overall, the goal of this project is to understand the role of DNA damage repair and the circadian clock in response to platinum-based chemotherapy. This knowledge could be used to provide more effective, targeted treatment plans for patients. This fellowship and my comprehensive individualized training plan will help start my career as an independently funded physician-scientist in the field of oncology.