Rational Approaches to Melanoma Therapy

项目概要-总体 该患者源性异种移植物（PDX）开发和试验中心（T-PDTC）的总体目标是 开发功能精确的组合疗法，可以转化为临床试验，以克服药物 耐药性，并产生长期反应，改善黑色素瘤患者的预后。黑素瘤 在过去的十年中，由于新的免疫和靶向治疗的可用性， 可用的治疗。使用BRAF和MEK抑制剂的靶向治疗已被批准用于患有以下疾病的患者： BRAFV 600 E/K突变，存在于约50%的皮肤黑色素瘤中。这些治疗引起临床 在约80%的BRAFV 600突变患者中有应答。但大多数患者最终会进步。此外，在 对于携带野生型BRAF的肿瘤患者没有有效的靶向治疗。因此，迫切需要 未满足的临床需求，开发有效的治疗方法，以预防或克服对当前FDA的耐药性- 批准的疗法。为了促进新的治疗策略的发展，可以转化为临床 在临床试验中，我们已经开发了广泛的PDX模型，反映了临床，组织学和遗传学特征。 黑色素瘤的异质性我们拥有超过500个PDX型号，是全球最大的PDX系列之一。 人类恶性肿瘤我们的初步研究表明，我们的PDX收集概括了分子 在患者中观察到异质性。该集合还包括从患有以下疾病的患者建立的PDX子集： 对靶向治疗和免疫治疗的内在和获得性耐药性以及罕见的黑色素瘤亚型。这些努力 已经产生了一个强大的临床前资源，以开发，完善和优先考虑新的功能精度 用于黑素瘤患者的组合疗法。该T-PDTC构成了一个多学科和多- 机构计划专注于使用和继续扩大我们的黑色素瘤PDX收集， 类器官，以确定新的治疗组合方法，将填补重要的临床空白。程序 由两个研究项目和三个核心组成，来自一个团队，该团队在整个 在过去的五年里，发表了影响力很大的合作论文。研究项目旨在开发 针对最具挑战性的黑色素瘤类型的功能性精确组合疗法：耐药黑色素瘤 目前的治疗和缺乏BRAF突变的肿瘤（BRAFWT）。我们将绘制出 我们的黑色素瘤PDX和类器官，通过整合DNA，RNA和蛋白质数据， 与其分子特征相匹配的疗法我们将开发和实施基于机制的临床前试验， 药物组合在我们的大组分子特征的PDX。为此，我们将重点关注NCI- 研究性新药（IND）药物，以推进黑色素瘤精确治疗，同时抵消耐药性 并产生持久的反应。我们期望获得新的药物生物学机理知识 耐药性黑色素瘤，这将导致改善和持久的精确治疗。我们希望能找到生物标记物 选择肿瘤进行特定治疗，并为早期临床试验提供数据驱动的建议。

Project Summary – Overall The overarching goal of this Patient Derived Xenograft (PDX) Development and Trial Center (T-PDTC) is to develop functional precision combination therapies that can be translated into clinical trials to overcome drug resistance and produce to long-term responses improving the outcomes of melanoma patients. The melanoma treatment landscape has radically improved in the past decade due to availability of new immune- and targeted- therapies available. Targeted therapies using BRAF and MEK inhibitors have been approved for patients with BRAFV600E/K mutations, which are present in ~50% of cutaneous melanomas. These treatments elicit clinical responses in ~80% of BRAFV600 mutant patients. However, most patients eventually progress. Additionally, there are no effective targeted therapies for patients whose tumors harbor wild-type BRAF. Thus, there is an urgent unmet clinical need to develop efficacious treatments to prevent or overcome resistance to current FDA- approved therapies. To facilitate the development of new therapeutic strategies that can be translated into clinical trials, we have developed a broad collection of PDX models that reflects the clinical, histological, and genetic heterogeneity of melanoma. Our collection of >500 PDX models represents one of the largest collections for any human malignancy. Our initial studies have demonstrated that our PDX collection recapitulates the molecular heterogeneity observed in patients. This collection also includes a subset of PDX established from patients with intrinsic and acquired resistance to targeted- and immune-therapies and rare melanoma subtypes. These efforts have generated a robust pre-clinical resource to develop, refine, and prioritize new functional precision combinatorial therapies for melanoma patients. This T-PDTC constitutes a multi-disciplinary and multi- institutional Program focused on the use and continued expansion of our melanoma PDX collection and organoids to identify new therapeutic combination approaches that will fill important clinical gaps. The Program consists of two research projects and three Cores from a team that has worked extremely well together over the last five years, publishing high-impact collaborative papers. The Research Projects are designed to develop functional precision combination therapies for the most challenging types of melanomas: those that are resistant to current therapies and tumors that lack BRAF-mutations (BRAFWT). We will map the molecular landscape of our melanoma PDXs and organoids by integrating DNA, RNA, and protein data to nominate combination therapies matching their molecular profile. We will develop and implement mechanism-based preclinical trials of drug combinations in our large set of molecularly characterized PDXs. To do this, we will focus on NCI- Investigational New Drug (IND) agents to advance melanoma precision therapy, while offsetting drug resistance and producing durable responses. We expect to gain new mechanistic knowledge about the biology of drug resistant melanoma that will lead to improved and durable precision therapies. We expect to identify biomarkers to select tumors for specific treatments and provide data-driven recommendations for early phase clinical trials.