An integrated translational approach to overcome drug resistance

克服耐药性的综合转化方法

• 批准号: 10005182
• 负责人: Ryan Bruce Corcoran
• 金额: $ 135.62万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005182
• 关键词: Address; Antineoplastic Agents; Area; Autopsy; Blood; Bypass; Cancer Patient; Cancer Therapy Evaluation Program; Clinic; Clinical; Clinical Trials; Drug Combinations; Drug Screening; Drug resistance; Evaluation; Future; Genetic; Heterogeneity; Immune checkpoint inhibitor; Institutes; Institution; Lung; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Mitogen-Activated Protein Kinase Inhibitor; Modeling; Molecular; Monitor; Pathway interactions; Patients; Receptor Protein-Tyrosine Kinases; Resistance; Stream; Therapeutic; Time; Tumor Tissue; Tumor-Derived; Tyrosine Kinase Inhibitor; Work; base; cancer type; checkpoint inhibition; design; exome sequencing; functional genomics; inhibitor/antagonist; innovation; liquid biopsy; melanoma; mouse model; novel; novel therapeutics; pre-clinical; programs; resistance mechanism; response; therapy resistant; transcriptome sequencing; translational approach; translational pipeline; trial design; tumor

Drug resistance represents one of the most critical obstacles to clinical benefit for cancer patients. Due to the size and complexity of this challenge, we believe a collaborative team approach is critical and have assembled a team of drug resistance experts from three leading institutions (MGH, the Broad Institute, and MIT/Koch Institute) with an exceptional track record of impactful discoveries in this field. We propose an integrated full-spectrum translational platform—including liquid biopsy, patient-derived tumor models, exome and transcriptome sequencing of tumor tissue, rapid autopsy, functional genomic screens, innovative preclinical mouse models, and a high-throughput combination drug-screening platform covering the CTEP portfolio—to address critical principles of drug resistance across several major cancer types—lung, melanoma and GI cancers, which impact a large percentage of cancer patients. Overall, these three projects will focus on the common theme of bypass resistance mechanisms, a critical ad frequent mechanism of therapeutic resistance that can involve both genetic and adaptive resistance mechanisms that “bypass” the effects of therapy, and which can drive both intrinsic and acquired resistance. To maximize the potential impact on cancer patients we will focus projects on three major tumor types—lung, melanoma and GI cancers—with each project integrating at least two tumor types. We will focus our projects on defining and overcoming key bypass resistance mechanisms to three of the most critical classes of cancer therapeutics: MAPK inhibitors, RTK inhibitors, and immune checkpoint inhibitors. While each project will focus on a specific therapy and at least two specific cancer types, we believe the overall program design can be readily applied to additional agents and molecularly-defined cancers, such that the ultimate impact of this work will go beyond the specific studies proposed and will serve as a “blueprint” for critical discoveries related to drug resistance. We anticipate that these efforts will define a new standard in our mechanistic understanding of bypass resistance mechanisms and will lead to novel opportunities to overcome them in the clinic. Our proposed approach will provide a steady stream of novel therapeutic strategies involving CTEP agents and pathways for evaluation in future clinical trials, as well as new potential agents for the CTEP portfolio. We have also integrated cutting-edge strategies for real-time blood-based monitoring of response and resistance to help guide innovative trial design.

耐药性是癌症患者临床受益的最关键障碍之一。由于 鉴于这一挑战的规模和复杂性，我们认为协作的团队方法至关重要，并已 来自三家领先机构(MGH、布罗德研究所和麻省理工学院/科赫)的耐药性专家团队 该研究所)在这一领域取得了卓有成效的发现的杰出记录。我们提出了一种集成的全谱 翻译平台-包括液体活检、患者来源的肿瘤模型、外显子组和 肿瘤组织的转录组测序、快速尸检、功能基因组筛选、创新的临床前 小鼠模型，以及涵盖CTEP产品组合的高通量组合药物筛选平台-TO 阐述几种主要癌症类型--肺癌、黑色素瘤和胃肠道疾病--耐药性的关键原则 癌症，这影响了很大比例的癌症患者。总体而言，这三个项目将集中于 旁路耐药机制的共同主题--治疗耐药的关键和常见机制 这可能涉及“绕过”治疗效果的遗传和适应性耐药机制，以及 它既可以驱动固有的抵抗，也可以驱动后天的抵抗。为了将对癌症患者的潜在影响最大化，我们 将专注于三种主要的肿瘤类型-肺癌、黑色素瘤和胃肠道癌症-每个项目都整合了 至少有两种肿瘤类型。我们的项目将重点放在定义和克服关键的旁路阻力上 三类最关键的癌症治疗药物的作用机制：MAPK抑制剂、RTK抑制剂和 免疫检查点抑制剂。虽然每个项目都将专注于一种特定的疗法和至少两种特定的 癌症类型，我们相信整个程序设计可以很容易地应用于其他药物和 分子定义的癌症，这样这项工作的最终影响将超越具体的研究 提出并将作为与耐药性相关的关键发现的“蓝图”。我们预料到 这些努力将在我们对旁路阻力机制的机械理解中定义一个新的标准 并将带来在临床上克服它们的新机会。我们提议的方法将提供一个 源源不断的新治疗策略，包括CTEP制剂和未来评估的途径 临床试验，以及CTEP产品组合的新潜在药物。我们还集成了尖端技术 基于血液的实时监测反应和耐药性的策略，以帮助指导创新试验 设计。