Combination Therapies to Defeat Melanoma Resistance

总体摘要 这是A1重新提交的一个新的计划项目补助金（PPG），重点是研究如何先进 黑色素瘤抵抗靶向治疗和免疫治疗，无论是在前期还是在一段时间的反应后， 这些信息旨在确定提供新的治疗机会的脆弱性。项目1 （Roger Lo）专注于研究NRASMUT黑色素瘤对靶向治疗的耐药性， 免疫疗法研究将集中在发现和共同靶向基因组，表观基因组和/或信号转导 引起MEK抑制剂（MEKi）抗性的改变;利用MEKi抗性克隆的MEKi成瘾; 以及鉴定免疫靶标以在NRASMUT中体内增强MEKi功效并抑制MEKi抗性 黑素瘤。项目2（托马斯格雷伯）的重点是研究分子机制和靶向的 临床前模型中去分化黑素瘤的铁凋亡敏感性。此外，该项目还将 定义和靶向黑色素瘤去分化的主要调控程序。项目3（Antoni Ribas） 专注于研究PD-1阻断免疫疗法的原发性和获得性耐药性，特别是定义 干扰素γ和抗原呈递途径的突变，以及逆转T细胞排斥 从癌症。对这些耐药机制的理解将使组合疗法合理化， 在临床前小鼠模型中进行了测试。这三个项目由三个核心支助，即行政和 统计学核心（Antoni Ribas）、生物标本核心（Begonya Comin-Anduix）和患者衍生 异种移植物（PDX）/同基因小鼠核心（Gatien Moriceau）。 拟议的研究解决了需要综合和协作团队的科学问题。在 项目1，MAPK抑制剂成瘾的研究，导致对药物的敏感性，诱导parthanatos（a 细胞死亡的半胱天冬酶非依赖性模式），可应用于在 项目2将与项目3中研究的免疫疗法协同作用。在项目2中， 去分化的黑色素瘤表型，这是对MAPK抑制剂的抗性机制，也诱导 T细胞释放的细胞因子，导致对铁凋亡（一种铁依赖性非凋亡细胞 死亡）诱导剂。项目1将在NRAS突变型黑色素瘤中探索这种耐药机制 以及项目3中抗PD 1耐药的黑色素瘤。反过来，项目3将寻求整合 项目1和2中的新概念和模型，考虑到诱导这些新概念和模型的可能免疫效应， 细胞死亡的形式。这项合作研究将需要共享患者来源的组织，模型系统， 在核心B和C的协助下，在每个项目中获得和开发的治疗团，以及 核心A的统计设计和支持。 1

OVERALL ABSTRACT This is the A1 re-submission of a new Program Project Grant (PPG) focused on studying how advanced melanoma resists targeted therapies and immunotherapies, either upfront or after a period of response, and this information is aimed at defining the vulnerabilities that provide new therapeutic opportunities. Project 1 (Roger Lo) focuses on the study of resistance of NRASMUT melanomas to targeted therapies and immunotherapies. Studies will focus on discovering and co-targeting genomic, epigenomic and/or signaling alterations causative of MEK inhibitor (MEKi) resistance; exploiting MEKi-addiction of MEKi-resistant clones; and identifying immune targets to augment MEKi efficacy and suppress MEKi resistance in vivo in NRASMUT melanomas. Project 2 (Thomas Graeber) focuses on studying molecular mechanisms and targeting of the ferroptosis sensitivity of dedifferentiated melanomas in preclinical models. In addition, this project will also define and target master regulatory programs underlying melanoma dedifferentiation. Project 3 (Antoni Ribas) focuses on studying primary and acquired resistance to PD-1 blockade immunotherapy, especially defining mutations in the interferon gamma and antigen presentation pathways, as well as reversing T cell exclusion from cancers. The understanding of these resistance mechanisms will rationalize combinatorial therapies to be tested in preclinical mouse models. The three projects are supported by three cores, the Administrative and Statistics Core (Antoni Ribas), the Biospecimen Core (Begonya Comin-Anduix) and the Patient-Derived Xenograft (PDX)/Syngeneic Mouse Core (Gatien Moriceau). The proposed research addresses scientific problems that require integrated and collaborative teamwork. In Project 1, the study of MAPK inhibitor addiction, resulting in sensitivity to drugs that induce parthanatos (a caspase-independent mode of cell death), can be applied to the melanoma dedifferentiation states studied in Project 2 and will synergize with immunotherapies studied in Project 3. Similarly, in Project 2, the dedifferentiated melanoma phenotype, which is a resistance mechanism to MAPK inhibitors and also induced by T cell-released cytokines, leads to sensitivity to ferroptosis- (an iron-dependent form of nonapoptotic cell death) inducing agents. This resistance mechanism will be explored in NRAS mutant melanoma in Project 1 and across melanoma with resistance to anti-PD1 in Project 3. Reciprocally, Project 3 will seek to integrate the new concepts and models from Projects 1 and 2, given the likely immune effects of inducing these new forms of cell death. This collaborative research will require sharing the patient-derived tissues, model systems, and therapeutic regiments acquired and developed in each Project, facilitated by Cores B and C, and statistical design and support from Core A. 1