Project 2

项目2

• 批准号: 10247525
• 负责人: Ryan Bruce Corcoran
• 金额: $ 27.55万
• 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/10247525
• 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）抑制剂已经彻底改变了几种癌症类型的治疗，但是 获得性抗性的最终出现仍然是临床益处的主要限制。我们最近的研究 研究小组和其他人已经表明，获得性耐药的特点往往是广泛的肿瘤， 异质性，在不同的肿瘤亚克隆中同时出现多种耐药机制， 一个病人。这种异质性是一个难以克服的治疗障碍，因为设计的治疗方法 克服一种特定的抗性机制可能无法抑制携带其他抗性机制的亚克隆。 抗性机制，导致克隆生长和治疗失败。制定和模拟战略， 克服对RTK抑制剂的异质性耐药性，我们将进行全面评估， 获得性耐MET抑制。MET是一种重要的RTK，其治疗重要性日益增加， 在约4%的MET治疗胃食管癌（GEC）中观察到MET抑制剂的显著反应 约5%的非小细胞肺癌（NSCLC）患者具有MET外显子14跳读。我们将 采用系统性液体活检平台进行循环肿瘤DNA分析，结合连续肿瘤 活组织检查和快速尸检程序，以确定获得性肿瘤的分子景观和异质性。 对MET抑制的抗性。通过详细的机制研究，我们将试图确定共同的 多种抗性机制汇聚的信号节点，这可能代表“普遍的” 目标是同时拦截多种异质耐药机制。我们还将评估 连续抑制策略结合实时ctDNA监测的潜力， 不共享共同信号输出的抗性机制。这些方法有可能 为克服获得性耐药背景下的肿瘤异质性创造了新的标准， 预期这些研究定义的原则将广泛适用于其他RTK抑制剂范例。