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Sensitization to Chemoradiation by Therapeutic Targeting of the DNA Damage Response

通过 DNA 损伤反应的治疗靶向来提高放化疗敏感性

基本信息

批准号：
9901492
负责人：
THEODORE S LAWRENCE
金额：
$ 58.21万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9901492
关键词：
Apoptotic Biological Assay Biological Markers Body Weight decreased CASP3 gene Cancer Therapy Evaluation Program Cell Cycle Checkpoint Cell Death Cell Line Cell Survival Cell model Cells Cellular Assay Characteristics Clinical Trials Collection Combined Modality Therapy Comet Assay DNA Damage DNA Double Strand Break DNA Repair DNA Repair Pathway DNA biosynthesis Data Defect Dependence Dominant Genetic Conditions Dose Dose-Limiting Double Strand Break Repair Drug Targeting Future Germ Cells Goals Gold Image Immune system Immunocompetent Investigation Magnetic Resonance Imaging Malignant neoplasm of pancreas Measures Mutation Nonhomologous DNA End Joining Normal Cell Normal tissue morphology Organ PRKDC gene Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Phosphotransferases Radiation Radiation Tolerance Reporter Safety Schedule Small Intestines Surrogate Markers TP53 gene Therapeutic Index Time Toxic effect Translating Treatment Efficacy Tumor Markers Validation Xenograft procedure advanced pancreatic cancer base cellular targeting chemoradiation chemotherapy clinical development design diffusion weighted efficacy study gastrointestinal gemcitabine high throughput screening human model imaging biomarker improved improved outcome in vivo inhibitor/antagonist intestinal crypt mouse model neoplastic cell pancreatic cancer cells pancreatic neoplasm pharmacodynamic biomarker pre-clinical predictive marker prevent response response biomarker standard of care targeted agent targeted biomarker targeted sequencing therapeutic target tissue injury treatment response tumor tumor growth

项目摘要

ABSTRACT There is an urgent need to improve the efficacy of chemoradiation therapy for patients with locally advanced pancreatic cancer (LAPC). Since unrepaired DNA double-strand breaks (DSB) are responsible for the majority of cell death in response to chemoradiation, targeting cellular DNA damage response (DDR) pathways is a promising approach to enhance the efficacy of chemoradiation therapy by preventing efficient repair of DNA damage, leading to loss of tumor cell viability. Since defects in the DDR such as P53 mutation occur in up to 70% of pancreatic ductal adenocarcinomas (PDAC), targeted inhibition of the DDR provides an opportunity to selectively enhance sensitivity to chemoradiation in tumor but not normal cells. The overall goal of our proposed study is to identify agents from the CTEP collection that modulate the cellular response to DNA damage and best sensitize tumor cells to standard of care chemoradiation therapy. To achieve this goal, we will in Aim 1 conduct an unbiased high throughput screen (HTS) in a panel of PDAC cell lines using a panel of agents from the CTEP collection that modulate the cellular DDR, including drugs that target ATR, DNAPK, PARP, and WEE1 (Aim 1A). An initial cell viability screen at various concentrations of single agents alone or in combination with chemoradiation will be conducted. In addition to concentration, optimal sequencing of targeted agents with chemoradiation will be investigated. A live cell assay for the DDR as well as apoptotic cell death will be utilized as orthogonal screens to assist in hit prioritization and validation. In Aim 1B, a group of agents selected by defined criteria will be further evaluated by conducting a “gold standard” clonogenic survival assay using a panel of PDAC cell lines. In Aim 1C we will conduct a normal cell counter screen using the above agents against normal cells to identify those which cause toxicity in combination with chemoradiation. The efficacy of these prioritized agents will be validated in Aim 1D using a panel of patient- derived xenograft (PDX) sphere explant cultures. Two agents with the optimal enhancement ratio (1B and 1D), and safety (1C) at the optimal concentration and schedule (1A and 1B) will be studied in Aim 2. We will compare the therapeutic efficacy of the nominated agents in combination with chemoradiation using both PDX and immune competent syngeneic mouse models of PDAC (Aim 2A). Normal tissue injury caused by these two agents (Aim 2B) will be evaluated, which together with tumor efficacy will lead to the choice of the agent to pursue in clinical trials. Aim 3 will delineate the mechanistic basis for the chemoradiation potentiating activity of the superior agent (Aim 3A) with the goal of selecting pharmacodynamic and imaging biomarkers (Aims 3B and 3C), using in vivo studies in mouse models, for the future clinical trial. Completion of these aims will provide the required preclinical data regarding efficacy, safety, and biomarkers of response (mechanistic- and imaging- based) for the rationale design of a future clinical trial for patients with LAPC.

抽象的迫切需要提高局部晚期患者放化疗的疗效胰腺癌（LAPC）。由于未修复的 DNA 双链断裂 (DSB) 是造成大多数细胞因放化疗而死亡，靶向细胞 DNA 损伤反应 (DDR) 途径是一种通过阻止 DNA 的有效修复来增强放化疗疗效的有前途的方法损伤，导致肿瘤细胞活力丧失。由于 DDR 中的缺陷（例如 P53 突变）最多发生在 70% 的胰腺导管腺癌 (PDAC)，靶向抑制 DDR 提供了机会选择性增强肿瘤细胞而非正常细胞对放化疗的敏感性。我们的总体目标拟议的研究是从 CTEP 集合中识别调节细胞反应的药物 DNA 损伤并使肿瘤细胞对标准放化疗更加敏感。为了实现这一目标为了实现目标，我们将在目标 1 中使用 PDAC 细胞系面板进行无偏高通量筛选 (HTS) CTEP 系列中调节细胞 DDR 的一组药物，包括针对 ATR 的药物， DNAPK、PARP 和 WEE1（目标 1A）。不同浓度单一试剂的初始细胞活力筛选单独进行或与放化疗联合进行。除了浓度之外，最佳将研究放化疗靶向药物的测序。 DDR 的活细胞检测因为凋亡细胞死亡将被用作正交筛选，以协助命中优先级排序和验证。瞄准 1B，根据定义的标准选择的一组代理将通过执行“黄金标准”进一步评估使用一组 PDAC 细胞系进行克隆存活测定。在目标 1C 中，我们将进行正常的细胞计数使用上述药物针对正常细胞进行筛选，以识别那些与以下药物组合引起毒性的药物：放化疗。这些优先药物的功效将在 Aim 1D 中使用一组患者进行验证衍生异种移植（PDX）球体外植体培养物。具有最佳增强比例的两种药剂（1B 和 1D），目标 2 将研究最佳浓度和时间表（1A 和 1B）下的安全性（1C）。我们将使用 PDX 比较提名药物与放化疗联合的治疗效果和具有免疫能力的 PDAC 同系小鼠模型（目标 2A）。这些引起的正常组织损伤将评估两种药物（目标 2B），这与肿瘤疗效一起将导致药物的选择追求临床试验。目标 3 将描述放化疗增强活性的机制基础优质药物（目标 3A），目标是选择药效学和成像生物标志物（目标 3B）和3C），使用小鼠模型的体内研究，用于未来的临床试验。完成这些目标将提供有关功效、安全性和反应生物标志物（机械和机制）所需的临床前数据基于成像）为 LAPC 患者未来临床试验的基本原理设计。