Elucidating Mechanisms of Resistance using Genetically Engineered Mouse Models

项目2：选择性突变型BRAF抑制剂在晚期糖尿病患者中的单药疗效 黑色素瘤通常都是短暂的，这说明治疗耐药是 菲尔德。认识到微环境环境影响肿瘤的生物学行为，包括 对治疗的反应，一种系统和全面的努力，以确定耐药机制。因此， 项目2为P01带来了精制生殖系和非生殖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的耐药基因以及临床前 可克服对选择性BRAF抑制剂(BRAFi)耐药性的联合治疗试验 黑色素瘤。 将实现以下3个目标：目标1：确定与赤霉病抗性有关的遗传事件 活着。在这里，使用我们精致的BRAF^(R)驱动的基因工程小鼠模型(GEMM)(IBIP)，我们 长期服用会产生一组敏感和耐药的黑色素瘤 布拉菲。这些肿瘤将接受深入的基因组特征分析，以确定候选病变 调停抵抗。候选人将优先考虑和验证/n WVO功能基因 基于统计意义和进化保守的筛选与比较 来自项目1的人类基因组数据。目标2：确定用于组合的共同灭绝目标 治疗BRAF*黑色素瘤。作为对目标1的补充，这一目标将采取全球性和不偏不倚的 发现共同灭绝目标的方法。我们将在中定义BRAF*监管的网络 黑色素瘤退化性遗传的动态转录组图谱对黑色素瘤的维持 突变BF^F*在IBIP小鼠体内的失活。目标3：制定合理的组合策略 在体内克服对BRAFi的抗性。这一目标是为了产生足够的临床前疗效。 激励一项新的18/11期临床试验的数据，该试验采用抑制共同灭绝的联合方案 和布拉菲一起瞄准目标。在这里，我们将使用鼠标模型来系统地筛选潜在的组合 最佳组合将在IBIP GEMM的临床前治疗试验中进行测试。 相关性(请参阅说明)： 黑色素瘤患者对选择性BRAF抑制剂的耐药性是当今临床面临的最大挑战。因此， 阐明调控反应和赋予抗性的机制是及时和相关的。带来 为了应对这一挑战，尖端基因组学和计算科学以及精炼的基因 经过改造的老鼠模型使人们能够做出公正和全面的发现努力。

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 BRAF^(R)¿¿^-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 compahson 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 BF^F* 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 18/11 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. RELEVANCE (See instructions): Resistance to selective BRAF inhibitors in melanoma is a paramount challenge in the clinics today. Thus, elucidating the mechanisms modulating response and conferring resistance is timely and relevant. Bringing to bear on this challenge cutting-edged genomics and computational science as well as refined genetically engineered mouse models enable a discovery effort that is unbiased and comprehensive.