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

项目总结/摘要 基于铂的化学疗法是实体瘤治疗的支柱。它们的作用机制是 最终导致细胞死亡的DNA加合物。不幸的是，这些药物有严重的副作用 并且耐药率很高;约40%的结肠直肠肿瘤对铂类耐药。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功效。一些 研究声称增强的DNA损伤修复是基于铂的化疗抗性的机制， 但目前的证据并不完整也不一致。此外，据推测， 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 铂类化疗;然而，更全面地了解这些相互作用是必要的， 优化治疗方案。该项目的总体目的是确定DNA损伤的作用 修复和昼夜节律的肿瘤反应铂为基础的化疗。为了解决这个问题， 间隙，桑卡尔实验室最近创建了测量全基因组加合物形成的方法， 以单核苷酸分辨率进行损伤修复。我假设在核苷酸切除上会有不同 铂敏感和铂耐药肿瘤模型之间以及不同昼夜节律时间的修复活性 点这些差异可能阐明修复和治疗时机在铂类缓解中的作用。目标1将 确定核苷酸切除修复在肿瘤对铂类化疗反应中的作用， 修复的数量和速度，以及铂耐药和铂敏感的全基因组修复模式 结肠直肠癌细胞系。这一目标的长期影响是提供一个更完整的理解， 核苷酸切除修复反应铂为基础的化疗，并确定修复签名，以更好地 了解治疗反应。目标2将探讨昼夜节律对铂类药物引起的损伤的影响 铂敏感和耐药患者异种移植物的修复模式。核苷酸切除修复是 受生物钟控制;从而探索治疗时机对修复的影响，以及这种影响如何 铂敏感型和耐铂型之间可能存在差异， 患者对铂类药物治疗的反应。长期目标是确定 最大化治疗指数。总的来说，这个项目的目标是了解DNA的作用， 损伤修复和生物钟对铂类化疗的反应。这些知识可能是 用于为患者提供更有效、更有针对性的治疗方案。这个奖学金和我的综合 个性化的培训计划将有助于开始我的职业生涯，作为一个独立资助的医生，科学家在该领域的 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.