An integrated translational approach to overcome drug resistance

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，我们认为合作团队的方法至关重要， 来自三个主要机构（MGH、Broad Institute和MIT/Koch）的耐药专家团队 研究所）在这一领域有着非凡的影响力发现记录。我们提出了一个集成的全光谱 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， 阐述几种主要癌症类型（肺癌、黑色素瘤和胃肠道癌）耐药性的关键原则 癌症，这影响了很大一部分癌症患者。总的来说，这三个项目将侧重于 旁路耐药机制的共同主题，治疗耐药的关键和常见机制 这可能涉及遗传和适应性耐药机制，“绕过”治疗的影响， 它可以驱动内在和获得的抵抗力。为了最大限度地发挥对癌症患者的潜在影响， 将重点关注三种主要肿瘤类型的项目-肺癌，黑色素瘤和胃肠道癌症-每个项目都将整合 至少两种肿瘤类型。我们将把我们的项目重点放在确定和克服关键的旁路阻力上 三种最关键的癌症治疗药物的机制：MAPK抑制剂，RTK抑制剂， 免疫检查点抑制剂。虽然每个项目将集中在一个特定的治疗和至少两个特定的 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， 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， 这一计划将成为与耐药性相关的重大发现的“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的标准 并将带来新的机会，以克服他们在临床上。我们建议的方法将提供一个 涉及CTEP药物和未来评估途径的新型治疗策略的稳定流 临床试验，以及CTEP产品组合的新的潜在药物。我们还整合了尖端的 基于血液的反应和耐药性实时监测策略有助于指导创新试验 设计

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.