Functional precision approaches to overcome intrinsic and acquired drug resistance in melanoma

项目摘要-项目1 尽管治疗黑色素瘤取得了重大进展，但只有不到30%的患者实现了长期治疗 几乎70%的患者对任何批准的治疗方法都有抵抗力，包括免疫疗法和靶向治疗 治疗。因此，迫切需要新的策略来克服内在和获得性耐药性。 患者衍生的异种移植(PDX)开发和试验中心(T-PDTC)研究项目将利用 关于我们广泛收集的经过临床注释和分子表征的&gt；500 PDX以开发功能性 抵消黑色素瘤耐药性的精确疗法。我们的工作假设是肿瘤的基因组， 有机化合物和PDX中的分子和药物反应谱可用于临床开发 可翻译的精确疗法。我们还假设，我们的临床前流水线将识别标记，以选择 最有可能对给定的治疗有反应，抵消耐药性并实现长期反应，而不是 明显的毒性。我们预计，我们的临床前研究将有助于确定靶向药物临床测试的优先顺序 黑色素瘤的治疗。 我们收集的黑色素瘤PDX具有广泛的生长特性、转移特性 通过靶向和整个外显子组测序，RNA表达和表达，形成体细胞突变 在与信号转导相关的~500个蛋白质中。我们的模型非常适合研究组合 克服或防止耐药性的治疗方法，因为它们代表了黑色素瘤的异质性。要做到这点， 提出了两个具体的目标：目标1，将检验耐药黑色素瘤携带有 与抗药性相关的转录签名，称为‘先天抗PD-1抗药性签名’(IPRES+) 对于抗PD1和MAPK抑制剂，BET和MEK抑制剂联合使用会产生反应。我们将对此进行优化 治疗方案，并进一步定义应答和耐药的标志物。对于IPRESNeg肿瘤，我们将整合 基因组、转录和蛋白质组学分析，将肿瘤与与其分子特征相匹配的药物配对；这 将允许建立最佳的组合和剂量策略。在目标2中，我们将进行时间和 空间转录和蛋白质组学分析，以识别和描述耐药亚群。我们的目标是监控 治疗反应和干预，使用旨在杀死大部分肿瘤和稀有药物的组合 耐性/持久亚群防止抗性的出现。我们预计，我们的研究将提供 将有效和持久的精确疗法从工作台转移到床边所需的关键信息 改善黑色素瘤患者的预后。

Project Summary – Project 1 Although significant progress has been made treating melanoma, less than 30% of patients achieve long-term responses and almost 70% of patients are resistant to any approved therapies including immunotherapies and targeted therapies. Therefore, novel strategies to overcome intrinsic and acquired drug resistance are sorely needed. This Patient Derived Xenograft (PDX) Development and Trial Center (T-PDTC) research project will capitalize on our extensive collection of >500 clinically annotated and molecularly characterized PDXs to develop functional precision therapies to offset melanoma drug resistance. Our working hypothesis is that the tumor’s genomic, molecular and drug response profiles in organoids and PDXs can be leveraged to develop clinically translatable precision therapies. We also posit that our pre-clinical pipeline will identify markers to select tumors that are most likely to respond to a given treatment, offsetting drug resistance and achieving long-term responses, with no overt toxicity. We expect that our pre-clinical studies will help prioritize the clinical testing of targeted agents for the treatment of melanoma. Our melanoma PDX collection has been extensively characterized for growth properties, metastasis formation, somatic mutations through targeted and whole exome sequencing, RNA expression and expression of ~500 proteins related to signal transduction. Our models are superbly suited to investigate combination therapies to overcome or prevent drug resistance as they represent the heterogeneity of melanoma. To do this, two Specific Aims are proposed: Aim 1, will test the hypothesis that drug resistant melanomas harboring a transcriptional signature termed ‘innate anti–PD-1 resistance signature’ (IPRES+), which is associated with resistance to anti-PD1 and MAPK inhibitors, will respond to the combination of BET and MEK inhibitors. We will optimize this treatment regimen and further define markers of response and resistance. For IPRESNeg tumors, we will integrate genomic, transcriptional and proteomic analyses to pair tumors with drugs matching their molecular profile; this will allow for establishing optimal combination and dosing strategies. In aim 2, we will conduct temporal and spatial transcriptomic and proteomic analysis to identify and profile drug tolerant subpopulations. Our goal is to monitor treatment response and intervene with combinations aimed at killing both the bulk of the tumor and rare drug tolerant/persister subpopulations preventing the emergence of resistance. We anticipate that our studies will provide critical information needed to translate effective and long-lasting precision therapies from the bench to bedside and improve the outcomes of melanoma patients.