Project-002

项目-002

• 批准号: 10247526
• 负责人: Ryan Bruce Corcoran
• 金额: $ 46.33万
• 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/10247526
• 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) 抑制剂彻底改变了多种癌症类型的治疗，但 最终出现获得性耐药仍然是临床获益的主要限制。我们最近的研究 小组和其他人已经表明，获得性耐药通常以广泛的肿瘤为特征 异质性，在不同的肿瘤亚克隆中同时出现多种耐药机制 个别患者。这种异质性带来了巨大的治疗障碍，因为旨在治疗的疗法 克服一种特定的耐药机制可能无法抑制含有其他耐药机制的亚克隆 耐药机制，导致克隆生长和治疗失败。制定战略并建立模型 克服对RTK抑制剂的异质耐药性，我们将进行全面评估 获得了对 MET 抑制的抗性。 MET 是一种关键的 RTK，其治疗重要性日益增强， 在大约 4% 的 MET 胃食管癌 (GEC) 中观察到 MET 抑制剂的显着反应 扩增和约 5% 的非小细胞肺癌 (NSCLC) 患者出现 MET 外显子 14 跳跃。我们将 采用系统液体活检平台进行循环肿瘤 DNA 分析，并结合连续肿瘤 活检和快速尸检程序，以确定获得的分子景观和异质性 对 MET 抑制的抵抗。通过详细的机制研究，我们将尝试识别常见的 多种抵抗机制汇聚的信号节点，可能代表“通用” 目标是同时拦截多种异质抵抗机制。我们还将评估 序贯抑制策略与实时 ctDNA 监测相结合的潜力可克服多种 不共享公共信号输出的阻力机制。这些方法有可能 在获得性耐药的情况下创建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 抑制剂范例。