An integrated translational approach to overcome drug resistance

克服耐药性的综合转化方法

• 批准号: 9985249
• 负责人: Ryan Bruce Corcoran
• 金额: $ 123.92万
• 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/9985249
• 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获益的最关键障碍之一。由于 鉴于这一挑战的规模和复杂性，我们认为协作团队方法至关重要，并且已经组建了 来自三个领先机构（麻省总医院、布罗德研究所和麻省理工学院/科赫研究所）的耐药性专家团队 研究所）在该领域具有影响力发现的卓越记录。我们提出了一个集成的全频谱 转化平台——包括液体活检、患者来源的肿瘤模型、外显子组和 肿瘤组织转录组测序、快速尸检、功能基因组筛选、创新临床前 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 解决几种主要癌症类型（肺癌、黑色素瘤和胃肠道癌）耐药性的关键原则 癌症，影响很大一部分癌症患者。总体而言，这三个项目将重点关注 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抵抗机制，以及 这可以驱动内在的和获得性的阻力。为了最大限度地提高对癌症患者的潜在影响，我们 将把项目重点放在三种主要肿瘤类型上——肺癌、黑色素瘤和胃肠道癌症——每个项目都整合 至少两种肿瘤类型。我们将把我们的项目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。虽然每个项目都将重点关注一种特定的疗法和至少两种特定的疗法 癌症类型，我们相信整体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，因此这项工作的最终影响将超越具体研究 提出并将作为与耐药性相关的关键发现的“蓝图”。我们预计 这些努力将为我们对旁路阻力机制的机械理解定义一个新标准 并将带来在临床上克服这些问题的新机会。我们提出的方法将提供 涉及 CTEP 药物和未来评估途径的源源不断的新治疗策略 临床试验以及 CTEP 产品组合的新潜在药物。我们还整合了尖端技术 基于血液的反应和耐药性实时监测策略，以帮助指导创新试验 设计。