Project-002

项目-002

• 批准号: 10005205
• 负责人: Ryan Bruce Corcoran
• 金额: $ 51.73万
• 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/10005205
• 关键词: Autopsy; Biopsy; Blood; Blood Circulation; Blood specimen; Bypass; CRISPR/Cas technology; Cancer Patient; Cell Culture Techniques; Clinical; Clinical Oncology; Clonal Evolution; Coupled; Culture Media; Custom; DNA analysis; Drug Combinations; Drug Screening; Drug resistance; Engineering; Exons; Genomics; Heterogeneity; In Vitro; Intercept; Lesion; Libraries; Methods; Modeling; Molecular; Monitor; Non-Small-Cell Lung Carcinoma; Open Reading Frames; Output; Patients; Protein Tyrosine Kinase; Receptor Protein-Tyrosine Kinases; Resistance; Sampling; Signal Transduction; Specimen; Therapeutic; Time; Treatment Failure; Tyrosine Kinase Inhibitor; cancer type; cell free DNA; experience; gastroesophageal cancer; in vivo; individual patient; inhibitor/antagonist; liquid biopsy; neoplastic cell; next generation sequencing; novel; prevent; programs; real time monitoring; receptor; resistance mechanism; response; therapeutic development; therapy design; therapy resistant; translational approach; tumor; tumor DNA; tumor heterogeneity

Receptor Tyrosine Kinase (RTK) inhibitors have revolutionized the treatment of several cancer types, but the eventual emergence of acquired resistance remains a major limitation of clinical benefit. Recent studies by our group and others have shown that acquired resistance is often characterized by extensive tumor heterogeneity, with multiple resistance mechanisms emerging simultaneously in distinct tumor subclones within an individual patient. This heterogeneity presents a formidable therapeutic obstacle, as therapies designed to overcome one specific resistance mechanism may be unable to suppress subclones harboring other resistance mechanisms, leading to clonal outgrowth and treatment failure. To develop and model strategies to overcome heterogeneous resistance to RTK inhibitors, we will perform a comprehensive assessment of acquired resistance to MET inhibition. MET is a critical RTK that is of growing therapeutic importance, with dramatic responses observed with MET inhibitors in the ~4% of gastroesophageal cancers (GEC) with MET amplification and ~5% of non-small cell lung cancer (NSCLC) patients with MET exon 14 skipping. We will employ a systematic liquid biopsy platform for circulating tumor DNA analysis, coupled with serial tumor biopsies, and a rapid autopsy program, to define the molecular landscape and heterogeneity of acquired resistance to MET inhibition. Through detailed mechanistic studies, we will attempt to identify common signaling nodes upon which multiple resistance mechanisms converge, which may represent “universal” targets to intercept multiple heterogeneous resistance mechanisms simultaneously. We will also evaluate the potential for sequential inhibition strategies coupled with real-time ctDNA monitoring to overcome multiple resistance mechanisms that do not share a common signaling output. These approaches have the potential to create a new standard for surmounting tumor heterogeneity in the setting of acquired resistance, and we anticipate that principles defined by these studies will be broadly applicable to other RTK inhibitor paradigms.

受体酪氨酸激酶（RTK）抑制剂已彻底改变了几种癌症类型的治疗 获得的抗药性的最终出现仍然是临床益处的主要限制。我们的最新研究 组和其他人表明，获得的抗性通常具有广泛的肿瘤特征 异质性，具有多种电阻机制，只是在不同的肿瘤亚克隆中出现 个体患者。这种异质性提出了强大的治疗障碍，因为旨在 克服一种特定的电阻机制可能无法抑制带有其他的子克隆 抗性机制，导致克隆出生和治疗失败。制定和建模策略 克服对RTK抑制剂的异质抗性，我们将对 获得了对抑制的抵抗力。 MET是一个关键的RTK，具有越来越重要的治疗意义 用MET的胃食管癌癌（GEC）观察到的MET抑制剂观察到的戏剧性反应 MET 14跳过的非小细胞肺癌（NSCLC）患者的扩增和约5％的非小细胞肺癌（NSCLC）。我们将 员工一个用于循环肿瘤DNA分析的系统液体活检平台，并与串行肿瘤结合 活检和快速尸检计划，以定义所获得的分子景观和异质性 对满足抑制的抵抗力。通过详细的机械研究，我们将尝试确定常见 信号传导节点在其上融合了多个电阻机制，这可能代表“通用” 仅仅拦截多种异构电阻机制的目标。我们还将评估 连续抑制策略以及实时ctDNA监测的潜力，以克服多个 不具有共同信号输出的电阻机制。这些方法有可能 创建一个在获得抵抗的环境下克服肿瘤异质性的新标准，我们 预计这些研究定义的原则将广泛适用于其他RTK抑制剂范式。