Rational approaches to melanoma therapy

项目概要-总体 转移性黑色素瘤患者的预后在过去十年中有了显著改善， 提高了对这种疾病的分子驱动因素的理解。特别是，多靶向治疗方案 已被批准用于BRAFV 600 E/K突变患者，约50%的皮肤黑色素瘤中存在BRAFV 600 E/K突变。 这些治疗在约80%的BRAFV 600 E/K突变患者中实现了临床应答，从而提供了证据- 个性化治疗策略的治疗潜力的概念。然而，大多数患者会 在开始这些治疗的两年内取得进展。此外，目前还没有靶向疗法， 在患有野生型BRAF的患者中显示有效。因此，开发治疗方法的临床需求尚未得到满足 预防或克服BRAFV 600 E/K突变患者对现有疗法的耐药性， 在没有BRAF突变的患者中有效。为了促进新的治疗策略的发展， 在过去的5年里，我们已经领导了一个主要的努力，开发了广泛的PDX模型，以反映临床， 组织学和遗传异质性。我们收集的>450 PDX模型代表了 最大的收集任何人类恶性肿瘤，我们的初步测试表明，收集准确 概括了在患者中观察到的致癌驱动因素和分子异质性。该集合还 包括从对靶向治疗具有获得性耐药性的患者中建立的PDX子集， 在体内维持这些药剂以维持它们的抗性表型。这些努力共同产生了一个 强大的资源，为患者开发，完善和优先考虑新的个性化组合疗法。因此我们 建议建立一个多学科和多机构的PDTC计划，重点是使用和继续 扩大我们的robutst黑色素瘤PDX收集，以确定新的治疗方法，填补重要的临床 这种疾病的差距。项目1将表征靶向受体酪氨酸激酶（RTK）的激酶抑制剂， PI 3 K-AKT通路联合获批靶向治疗在未经治疗和药物治疗的PDX模型中的应用 BRAFV 600 E/K突变型黑色素瘤。项目2将描述靶向癌症的凋亡机制 细胞作为在具有和不具有BRAFV 600 E/K突变的PDX中与MAPK途径抑制剂的组合方法， 包括抗凋亡基因异常的亚群。这两个项目都将利用 PDX模型，用于识别敏感性和耐药性的潜在生物标志物，以指导个性化患者选择， 未来的临床试验此外，还将分析肿瘤的治疗诱导效应（与敏感性相关） 鉴定的抗性机制和潜在的新组合策略。最后，标记中确定的 临床前模型将与入组的转移性黑色素瘤患者的平行生物标志物研究进行比较， 使用相同药物的临床试验。这些研究将得到PDX、生物信息学和 行政核心，以确保他们的成功，沿着一个试点项目计划，以开辟新的调查领域。 这些研究将有很大的潜力转化为新的个性化临床试验。

Project Summary – Overall The outcomes of patients with metastatic melanoma have improved dramatically over the last decade due to an improved understanding of the molecular drivers of this disease. In particular, multiple targeted therapy regimens have been approved for patients with a BRAFV600E/K mutation, which are present in ~50% of cutaneous melanomas. These treatments achieve clinical responses in ~80% of patients with a BRAFV600E/K mutation, thus providing proof- of-concept of the therapeutic potential for personalized therapeutic strategies. However, most of the patients will progress within 2 years of starting those therapies. Further, currently there are no targeted therapies that have been shown to be effective in patients with a wild-type BRAF. Thus, there are unmet clinical needs to develop treatments that prevent or overcome resistance to existing therapies for patients with a BRAFV600E/K mutation, and that are effective in patients without a BRAF mutation. In order to facilitate the development of new therapeutic strategies, over the last 5 years we have led a major effort to develop a broad collection of PDX models to reflect the clinical, histological, and genetic heterogeneity of this disease. Our collection of >450 PDX models represents one of the largest collections for any human malignancy, and our initial testing demonstrates that the collection accurately recapituluates the oncogenic drivers and molecular heterogeneity that is observed in patients. This collection also includes a subset of PDX established from patients with acquired resistance to targeted therapies that have been maintained on those agents in vivo to sustain their resistant phenotype. Together these efforts have generated a robust resource to develop, refine, and prioritize new personalized combinatorial therapies for patients. Thus, we propose to establish a multi-disciplinary and multi-institutional PDTC Program focused on the use and continued expansion of our robutst melanoma PDX collection to identify new therapeutic approaches that fill important clinical gaps in this disease. Project 1 will characterize kinase inhibitors targeting receptor tyrosine kinases (RTKs) and the PI3K-AKT pathway in combination with approved targeted therapies in PDX models in treatment-naïve and drug- resistant BRAFV600E/K-mutant melanomas. Project 2 will characterize targeting the apoptotic machinery of cancer cells as a combinatorial approach with MAPK pathway inhibitors in PDX with and without BRAFV600E/K mutations, including in subsets with aberrancies in anti-apoptotic genes. Both Projects will utilize baseline characteristics of the PDX models to identify potential biomarkers of sensitivity and resistance to guide personalized patient selection for future clinical testing. In addition, tumors will be analyzed for treatment-induced effects that correlate with sensitivity to identified resistance mechanisms and potential new combinatorial strategies. Finally, markers identified in the preclinical models will be compared to parallel biomarker studies of metastatic melanoma patients enrolled in clinical trials utilizing the same agents. These studies will be supported by the PDX, Bioinformatics, and Administrative Cores to ensure their success, along with a Pilot Project program to open new areas of investigation. Together these studies will have high potential to translate into new personalized clinical trials for patients.