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

项目摘要/摘要 以铂为基础的化疗是实体肿瘤治疗的主要手段。它们的作用机制是形成 DNA加合物最终会导致细胞死亡。不幸的是，这些药物有严重的副作用。 而且耐药率很高；大约40%的结直肠肿瘤对铂类药物耐药。了解 耐药性的分子机制可以通过对抗耐药性来帮助最大限度地发挥疗效。一批 研究称，DNA损伤修复增强是铂类化疗耐药的一种机制， 但到目前为止，证据并不完整，也不一致。此外，人们还假设， 基于核苷酸切除修复的昼夜节律控制的铂治疗将改善肿瘤对 以铂为基础的化疗；然而，有必要更全面地了解这些相互作用 以优化治疗方案。这个项目的总体目的是确定DNA损伤的作用 铂为基础的化疗对肿瘤反应的修复和昼夜节律。要解决这一知识 GAP，桑卡实验室最近创造了测量全基因组加合物形成和 单核苷酸分辨率下的损伤修复。我假设在核苷酸切除方面会有不同 不同昼夜节律下铂敏感和铂耐药肿瘤模型的修复活性 积分。这些差异可能阐明修复和治疗时机在铂类药物反应中的作用。目标1将 通过确定核苷酸切除修复在肿瘤对铂类化疗反应中的作用 铂耐药和铂敏感株的修复数量和修复速度，以及全基因组修复模式 结直肠癌细胞株。这一目标的长期影响是为了更全面地了解 核苷酸切除修复对铂类化疗的反应和识别修复信号以更好地 了解治疗反应。目标2将探讨昼夜节律对铂损伤的影响 铂敏感和耐药患者来源的异种移植物的修复模式。核苷酸切除修复是 由生物钟控制；从而探索治疗时机对修复的影响，以及这种影响是如何 铂敏感型和耐铂型之间可能存在差异，这对于全面了解 患者对铂类药物治疗的反应。长期目标是确定最佳时机 治疗以最大限度提高治疗指数。总体而言，这个项目的目标是了解DNA的作用 损伤修复和生物钟对铂为基础的化疗的反应。这一知识可能是 用于为患者提供更有效、更有针对性的治疗计划。这份奖学金和我的综合 个性化的培训计划将帮助我开始自己的职业生涯，成为一名独立资助的内科医生-科学家，在 肿瘤学。

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.