Project 1: Strategies to enhance MEK inhibitor efficacy in MUTNRAS melanoma

项目 1：增强 MEK 抑制剂对 MUTNRAS 黑色素瘤疗效的策略

基本信息

批准号：
10261396
负责人：
ROGER S LO
金额：
$ 51.79万
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/10261396
关键词：
Agonist Antibodies Biological Markers Biology CTLA4 gene Cell Death Cell Line Cells Chromatin Clinical Clinical Research Clinical Trials Collaborations Combined Modality Therapy Correlative Study DNA Repair Data Dermatology Dose Enrollment Evolution Exposure to Generations Genome Human Immunotherapy Joints Laboratories Letters Life MAP Kinase Gene MEKs Measures Melanoma Cell Modeling Monitor Multiomic Data Mutation Natural Immunity Nivolumab Oncology PD-1 inhibitors Pathway interactions Patients Pharmacology Phase Phenotype Poly(ADP-ribose) Polymerases Proteome Protocols documentation Publications Reagent Refractory Regimen Resistance Resistance development Rotation Safety Sampling Stimulator of Interferon Genes Technical Expertise Testing Tissues Translating Withdrawal addiction anti-CTLA-4 therapy anti-CTLA4 anti-PD-1 anti-PD1 antibodies anticancer research base cancer therapy clinically relevant combinatorial design dimer exome human subject immune checkpoint immune checkpoint blockade immune resistance immunogenic cell death improved in vivo inhibitor/antagonist insight investigator-initiated trial melanoma methylome multiple omics neoplastic cell next generation participant enrollment patient derived xenograft model phase 2 study potential biomarker preclinical study preclinical trial predictive marker prevent programmed cell death protein 1 research clinical testing resistance mechanism response single-cell RNA sequencing small molecular inhibitor standard of care targeted treatment therapy resistant transcriptome tumor tumor microenvironment

项目摘要

PROJECT 1 ABSTRACT Mutation-targeted small molecular inhibitors and immune checkpoint blockade or ICB (anti-PD-1 and -CTLA-4 antibodies) have extended the quality and quantity of life for patients with advanced BRAFMUT melanoma. Beyond ICB, which is ineffective in up to 60% of patients, patients with advanced NRASMUT melanoma have no standard- of-care options. Due to the rapid onset of resistance, MEK inhibitor (MEKi) monotherapy has limited clinical activity against NRASMUT melanoma, with the potential exception of those melanoma previously exposed to ICB (the NEMO trial). Here, we propose to design MEKi-based combinatorial-sequential regimens against advanced NRASMUT melanoma. First, we will test the concept of priming MEKi responsiveness via anti-PD-1/L1 pretreatment (regardless of anti-PD-1/L1 sensitivity). We will test this concept as well as dissect the mechanisms of action and innate/acquired resistance in human subjects (by conducting a phase II investigator-initiated trial) and in syngeneic melanoma models. Second, we will test the concept of combining a next-generation RAF inhibitor (RAFi) with a MEKi to overcome and to prevent MEKi resistance. These studies will be conducted in human melanoma cell lines, patient-derived xenografts (PDXs), and syngeneic models. Third, we will test the concept of overcoming MEKi resistance by pharmacologically exploiting a hallmark vulnerability of resistant tumors: MEKi-addiction or tumor cell death induced by MEKi withdrawal. Specifically, to induce the regression of a diverse array of NRASMUT MEKi-resistant PDX models, we will test one strategy involving sequencing from a MEKi to a poly-ADP ribose polymerase inhibitor (PARPi) or another strategy involving rotations between MEKi and PARPi. We will also test whether these sequencing/rotational strategies, by inducing various extents of immunogenic cell death and/or innate immunity, would sensitize NRASMUT melanoma to combined anti-PD-1/L1 therapy. In these clinical and preclinical studies, we will derive multi-omic data and evaluate candidate pathways to identify predictive biomarkers. In addition to bulk tumor-based, multi-omic analysis (exome, genome, transcriptome, methylome, chromatin accessibility, proteome, TCR clonotypes) of longitudinal tumor samples, we will also dissect the single-cell (scRNA-seq, CyTOF) evolution of NRASMUT melanoma to identify additional combinatorial-sequential targets to overcome and then to prevent resistance. These studies require a close collaboration with Projects 2 and 3 and Cores A-C at levels of shared technical expertise, reagents/models and preliminary data, and this collaboration is grounded on a 10-year track record of joint publications that have resulted in deep insights into clinically relevant melanoma biology, multiple clinical trials and even approved therapies. The combination of oncology and dermatology expertise (Ribas and Lo) and laboratories with complementary approaches (Ribas, Lo, Graeber) promises to accelerate scientific concepts to clinical testing.

项目 1 摘要针对突变的小分子抑制剂和免疫检查点阻断或 ICB（抗 PD-1 和 -CTLA-4 抗体）延长了晚期 BRAFMUT 黑色素瘤患者的生活质量和数量。超过 ICB对高达60%的患者无效，晚期NRASMUT黑色素瘤患者没有标准- 护理选项。由于耐药发生迅速，MEK抑制剂（MEKi）单药治疗在临床上受到限制针对 NRASMUT 黑色素瘤的活性，但先前接触过 ICB 的黑色素瘤可能除外（NEMO 试验）。在这里，我们建议设计基于 MEKi 的组合序贯方案来对抗先进的 NRASMUT 黑色素瘤。首先，我们将测试通过抗 PD-1/L1 启动 MEKi 反应性的概念预处理（无论抗 PD-1/L1 敏感性如何）。我们将测试这个概念并剖析其机制人类受试者的行动和先天/后天抵抗力（通过进行 II 期研究者发起的试验）以及同基因黑色素瘤模型中。其次，我们将测试结合下一代英国皇家空军的概念抑制剂（RAFi）与 MEKi 一起克服和预防 MEKi 耐药性。这些研究将在人类黑色素瘤细胞系、患者来源的异种移植物 (PDX) 和同基因模型。第三，我们将测试通过药理学利用耐药性的标志性脆弱性来克服 MEKi 耐药性的概念肿瘤：MEKi 成瘾或 MEKi 戒断诱导的肿瘤细胞死亡。具体来说，诱导回归在一系列不同的 NRASMUT MEKi 抗性 PDX 模型中，我们将测试一种涉及测序的策略 MEKi 与聚 ADP 核糖聚合酶抑制剂 (PARPi) 或涉及 MEKi 之间轮换的其他策略和 PARPi。我们还将通过诱导不同程度的免疫原性细胞死亡和/或先天免疫，将使 NRASMUT 黑色素瘤对联合抗 PD-1/L1 敏感治疗。在这些临床和临床前研究中，我们将获得多组学数据并评估候选途径识别预测生物标志物。除了基于大量肿瘤的多组学分析（外显子组、基因组、纵向肿瘤样本的转录组、甲基化组、染色质可及性、蛋白质组、TCR 克隆型），我们还将剖析 NRASMUT 黑色素瘤的单细胞（scRNA-seq、CyTOF）进化，以确定其他克服然后防止阻力的组合顺序目标。这些研究需要密切与项目 2 和 3 以及核心 A-C 在共享技术专业知识、试剂/模型和初步数据，此次合作以 10 年的联合出版物记录为基础深入了解临床相关的黑色素瘤生物学、多项临床试验，甚至获得批准疗法。肿瘤学和皮肤科专业知识（Ribas 和 Lo）与实验室的结合补充方法（Ribas、Lo、Graeber）有望加速科学概念的临床测试。