Elucidating Mechanisms of Resistance using Genetically Engineered Mouse Models

使用基因工程小鼠模型阐明耐药机制

• 批准号: 8736408
• 负责人: LYNDA CHIN
• 金额: $ 28.51万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8736408
• 关键词: BRAF gene; Behavior; Biological; Bypass; Clinic; Clinical Trials; Complement; Computational Science; Data; Dependence; Dependency; Engineering; Event; Extinction (Psychology); Functional disorder; Gene Expression Profile; Genes; Genetic; Genetic Engineering; Genetic Screening; Genetically Engineered Mouse; Genomic Instability; Genomics; Germ Lines; Goals; Human; Immune; Kinetics; Lesion; Libraries; Life; Maintenance; Massive Parallel Sequencing; Mediating; Modeling; Mus; Pathway interactions; Patients; Phase; Proteomics; Regimen; Regressing Melanoma; Resistance; Sampling; Technology; Telomerase; Testing; Therapeutic; Therapy Clinical Trials; Ursidae Family; Validation; Withdrawal; base; cohort; exome; functional genomics; improved; in vivo; inhibitor/antagonist; melanoma; mouse model; mutant; neoplastic cell; novel; pre-clinical; preclinical efficacy; resistance mechanism; response; telomere; tumor; tumor growth

Project 2: The single agent efficacy of selective mutant BRAF inhibitors in patients with advanced melanoma is uniformly short-lived, illustrating that therapeutic resistance is a paramount question in the field. Recognizing that micro-environmental context influences the biological behavior of a tumor, including response to therapy, a systematic and comprehensive effort to identify mechanisms of resistance. Thus, Project 2 brings to this P01 the uses of refined germline and non-germline genetically engineered models of BRAF-driven melanomas for discovery and validation of novel resistant genes as well as for preclinical therapeutic testing of combinations that can overcome resistance to selective BRAF inhibitor (BRAFi) in melanoma. The following 3 aims will be pursued: Aim 1: Identify genetic events conferring resistance to BRAFi in vivo. Here, using our refined BRAFV600E-driven genetically engineered mouse model (GEMM) ("iBIP"), we will generate a longitudinal cohort of sensitive and resistant melanomas upon long-term administration of BRAFi. These tumors will be subjected to deep genomic characterization to identify candidate lesions mediating resistance. Candidates will be prioritized and validated for/n wVo functional genetic screening based on statistical significance as well as evolutionary conservation through comparison with human genomic data from Project 1. Aim 2: Identify co-extinction targets for combination therapeutics against BRAF* melanoma. Complementing Aim 1, this aim will take a global and unbiased approach to the discovery of co-extinction targets. We will define the BRAF* regulated network in melanoma maintenance through kinetic transcriptome profiling of regressing melanomas upon genetic inactivation of mutant BFAF* in IBIP mice. Aim 3: Develop rational combination strategies for overcoming resistance to BRAFi in vivo. The goal of this aim is to generate sufficient preclinical efficacy data to motivate a novel Phase 1B/II clinical trial on a combination regimen that inhibits a co-extinction target along with BRAFi. Here, we will use mouse models to systematically screen potential combinations for efficacy; the best combination will then be tested in preclinical therapeutic trials in the IBIP GEMM.

项目2：选择性突变型BRAF抑制剂对晚期晚期患者的单药疗效 黑色素瘤的寿命普遍较短，这说明治疗耐药性是该领域最重要的问题。 场地。认识到微环境影响肿瘤的生物学行为，包括 对治疗的反应，是识别耐药机制的系统和全面的努力。因此， 项目 2 为 P01 带来了精炼种系和非种系基因工程模型的使用 BRAF 驱动的黑色素瘤用于发现和验证新型耐药基因以及临床前研究 可以克服对选择性 BRAF 抑制剂 (BRAFi) 耐药性的组合的治疗测试 黑色素瘤。 将追求以下 3 个目标： 目标 1：识别赋予 BRAFi 抗性的遗传事件 体内。在这里，使用我们精制的 BRAFV600E 驱动的基因工程小鼠模型 (GEMM)（“iBIP”），我们 长期施用后将产生敏感和耐药黑色素瘤的纵向队列 布拉菲。这些肿瘤将接受深度基因组表征，以确定候选病变 调解阻力。候选人将被优先考虑并验证/n wVo 功能遗传 基于统计显着性和进化保守性的筛选 来自项目 1 的人类基因组数据。目标 2：确定组合的共同灭绝目标 针对 BRAF* 黑色素瘤的疗法。作为目标 1 的补充，该目标将采取全球性和公正的态度 发现共同灭绝目标的方法。我们将定义 BRAF* 监管网络 通过基因回归黑色素瘤的动力学转录组分析来维持黑色素瘤 IBIP 小鼠中突变 BFAF* 失活。目标3：制定合理的组合策略 克服体内对 BRAFi 的耐药性。该目标的目标是产生足够的临床前疗效 数据激发了一项关于抑制共灭绝的组合方案的新型 1B/II 期临床试验 与 BRAFi 一起定位。在这里，我们将使用小鼠模型来系统地筛选潜在的组合 为了功效；然后，最佳组合将在 IBIP GEMM 的临床前治疗试验中进行测试。