Combination Therapies to Defeat Melanoma Resistance

击败黑色素瘤耐药性的联合疗法

基本信息

批准号：
10025135
负责人：
ANTONI RIBAS
金额：
$ 257.47万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-11 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10025135
关键词：
Address Antigen Presentation Pathway BRAF gene Back Bioinformatics Biological Models Biology Caspase Cell Death Clinic Clinical Clinical Trials Collaborations Combined Modality Therapy Communities Databases Development Exclusion Experimental Models Genomics Goals Immune Immune Targeting Immunotherapy Institute of Medicine (U.S.)Interferon Type II Iron Knowledge Lead Letters MAP Kinase Gene MEKs Malignant Neoplasms Mitogen-Activated Protein Kinase Inhibitor Modeling Molecular Mus Mutation Neoplasm Metastasis Organ PD-1 blockade Patients Pharmaceutical Preparations Phenotype Pre-Clinical Model Program Research Project Grants Published Comment Research Research Project Grants Resistance Sampling Signal Transduction Site System T-Lymphocyte Testing Therapeutic Tissue Model Xenograft procedure addiction anti-PD-1 anti-PD1 therapy base clinical translation combinatorial cytokine design epigenomics immune checkpoint blockade improved in vivo inhibitor/antagonist innovation melanoma mouse model mutant new combination therapies next generation novel novel therapeutics pre-clinical prevent programs research clinical testing resistance mechanism response statistics targeted treatment

项目摘要

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

总体摘要这是新项目拨款 (PPG) 的 A1 重新提交，重点研究如何先进黑色素瘤对靶向治疗和免疫疗法有抵抗力，无论是在反应前还是在反应一段时间后，该信息旨在确定提供新治疗机会的脆弱性。项目1 (Roger Lo) 专注于 NRASMUT 黑色素瘤对靶向治疗的耐药性研究免疫疗法。研究将侧重于发现和共同靶向基因组、表观基因组和/或信号传导导致 MEK 抑制剂 (MEKi) 耐药性的改变；利用 MEKi 抗性克隆的 MEKi 成瘾性；并在 NRASMUT 中识别免疫靶点以增强 MEKi 功效并抑制体内 MEKi 耐药性黑色素瘤。项目 2（Thomas Graeber）专注于研究分子机制和靶向临床前模型中去分化黑色素瘤的铁死亡敏感性。此外，该项目还将定义和瞄准黑色素瘤去分化的主要监管计划。项目 3（安东尼·里巴斯）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 细胞排斥来自癌症。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。这三个项目得到三个核心的支持：行政和统计核心 (Antoni Ribas)、生物样本核心 (Begonya Comin-Anduix) 和患者衍生的异种移植（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合作的科学问题。在项目 1，研究 MAPK 抑制剂成瘾，导致对诱发 parthanatos 的药物敏感（a 不依赖半胱天冬酶的细胞死亡模式），可应用于研究中的黑色素瘤去分化状态项目 2 将与项目 3 中研究的免疫疗法产生协同作用。同样，在项目 2 中，去分化黑色素瘤表型，这是 MAPK 抑制剂的耐药机制，也诱导 T 细胞释放的细胞因子导致对铁死亡（一种铁依赖性非凋亡细胞形式）的敏感性死亡）诱导剂。项目1将在NRAS突变黑色素瘤中探索这种耐药机制以及项目 3 中对抗 PD1 具有抗药性的黑色素瘤。相反，项目 3 将寻求整合考虑到引入这些新概念和模型可能产生的免疫效应，项目 1 和 2 中的新概念和模型细胞死亡的形式。这项合作研究需要共享患者来源的组织、模型系统、在核心 B 和 C 的推动下，在每个项目中获得和开发的治疗方案，以及统计设计和核心 A 的支持。 1