Role of Tumor Stroma in Therapeutic Response and Resistance

描述（由申请人提供）：选择性突变BRAF抑制剂在晚期黑色素瘤患者中的单药疗效是一个变革性的进步，但一致的短期反应现在已经将治疗耐药性定义为该领域的核心问题。虽然该领域的大部分研究都集中在可以驱动耐药性的黑色素瘤细胞的体细胞改变上，但我们假设肿瘤微环境在决定最初对治疗的反应和随着时间的推移促进耐药性的出现方面起着积极的作用，因此调节肿瘤基质改变与靶向治疗一起是一种合理的组合策略，可以最大限度地减少耐药性的出现。为了系统地解决这个问题，我们汇集了U54团队，他们在黑色素瘤生物学和遗传学、免疫学和癌症基因组学领域的临床、转化和基础研究方面具有多样化但互补的专业知识，以开展以下两个高度相互依存和相互关联的项目。项目1：鉴定BRAF突变黑色素瘤中具有耐药性的基质改变。在本研究中，与基因工程小鼠模型中的类似分析相比，对BRAF突变的人类黑素瘤和衍生细胞在基线、治疗后和复发时的转录组学、表观基因组学和蛋白质组学水平进行全球无偏分析，将确定与依赖于肿瘤基质相互作用的耐药性相关的候选基质改变。这些候选药物的功能相关性将通过体外和体内的遗传或药理学扰动来验证，而人类的相关性将通过分析更大的人类样本队列来证实。最后，将探讨作用机制，以支持调节这些基质成分以减少耐药性的可能策略。项目2：免疫调节通路在BRAF靶向治疗耐药中的作用。免疫抑制通路阻断在人黑色素瘤中的临床疗效得到了人体和小鼠的初步数据支持，表明免疫抑制在黑色素瘤的发病过程中具有积极作用。该项目将研究免疫调节途径（通过CTLA4和PD-L1等分子）在黑色素瘤中的作用，并探索这种调节对治疗反应的影响。“用于TMEN研究的临床注释人类黑色素瘤”和“用于TMEN研究的GEM模型”这两个共享资源核心不仅将支持这两个项目的活动，而且有望成为整个研究网络的高影响力推动者。最后，U54团队为TMEN带来了多种独特的能力，可以用于肿瘤微环境的研究，因此，除了确保该中心内互补活动的密切互动和协调外，“行政核心”也将负责

DESCRIPTION (provided by applicant): The single agent efficacy of selective mutant BRAF inhibitors in patients with advanced melanoma is a transformative advance but the uniformly short-lived responses have now defined therapeutic resistance as the central paramount question in the field. While much of the field is focusing on somatic alterations in the melanoma cells that can drive resistance, we hypothesize that the tumor microenvironment plays an active contributory role in dictating the response to therapy initially and in facilitating emergence of resistance over time, hence modulating tumor-stromal alterations together with targeted therapy is a rational combination strategy to minimize emergence of resistance. To address this systematically, we have brought together this U54 team with diverse but complementary expertise in clinical, translational and basic research in areas of melanoma biology and genetics, immunology and cancer genomics to pursue the following two highly inter dependent and interrelated projects. Project 1: Identification of resistance-conferring stromal alterations i BRAF mutant melanoma. Here, global unbiased profiling on transcriptomic, epigenomic and proteomic levels in BRAF mutant human melanomas and derivative cells at baseline, post-treatment and upon relapse on selective BRAF inhibitor, compared with similar analyses in genetically engineered mouse models, will identify candidate stromal alterations associated with resistance that are dependent on tumor stromal interactions. Functional relevance of these candidates will be validated through genetic or pharmacological perturbation in vitro and in vivo while human relevance will be confirmed through analysis of larger cohort of human samples. Finally, mechanism of action will be explored to support possible strategy of modulating such stromal components to minimize resistance. Project 2: Roles of immune regulatory pathways in resistance to BRAF targeted therapy. Clinical efficacy of immune-inhibitory pathway blockade in human melanoma, supported by preliminary data in human and mouse, has pointed to an active role for immunosuppression in melanoma pathogenesis. This project will study the roles of immune regulatory pathways (through molecules such as CTLA4 and PD-L1) in melanoma and explore the consequences of such modulation on therapeutic response. The two Shared Resource Cores on "Clinically annotated human melanoma for TMEN research" and "GEM models for TMEN research" will not only support activities of these two projects but are expected to be high impact enablers for the entire research network. Finally, this U54 team brings to TMEN a diverse set of unique capabilities that can be leveraged for studies of the tumor microenvironment Thus, in addition to ensuring close interaction and coordination of complementary activities within this center, the 'Administrative Core' will also be responsible for efficient and effective communication and interaction with the TMEN research network.