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

• 批准号: 10025136
• 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
• 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/10025136
• 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; Xenograft Model; Xenograft procedure; 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; 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

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 突变靶向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。超越 ICB在高达60%的患者中无效，晚期NRASMUT黑色素瘤患者没有标准- 护理选项。由于耐药发生得很快，MEK抑制剂(Meki)单一疗法限制了临床应用 抗NRASMUT黑色素瘤活性，但以前接触ICB的黑色素瘤可能除外 (Nemo审判)。在这里，我们建议设计基于Meki的组合-序贯方案来对抗晚期 NRASMUT黑色素瘤。首先，我们将测试通过抗PD-1/L1来启动Meki反应性的概念 预处理(不考虑抗PD-1/L1敏感性)。我们将测试这一概念，并剖析其机制 在人类受试者中的作用和先天/后天抵抗力(通过进行由研究者发起的第二阶段试验) 在同基因黑色素瘤模型中。第二，我们将测试将下一代英国皇家空军 抑制剂(Rafi)用麦基来克服和预防麦基耐药性。这些研究将在#年进行 人类黑色素瘤细胞系、患者来源的异种移植(PDX)和同基因模型。第三，我们将测试 通过药理学利用耐药的标志性脆弱性来克服Meki耐药性的概念 肿瘤：麦基成瘾或因麦基戒断而导致的肿瘤细胞死亡。具体地说，为了诱导倒退 在一系列不同的NRASMUT耐Meki PDX模型中，我们将测试一种策略，涉及从 从Meki到多ADP核糖聚合酶抑制剂(PARPI)或其他涉及Meki之间旋转的策略 和帕尔皮。我们还将测试这些排序/轮换策略是否通过诱导不同程度的 免疫原性细胞死亡和/或天然免疫会使NRASMUT黑色素瘤对联合抗PD-1/L1敏感 心理治疗。在这些临床和临床前研究中，我们将获得多组数据并评估候选路径。 以确定预测性生物标记物。除了基于大量肿瘤的多组学分析(外显子组，基因组， 转录组、甲基组、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 组合-序贯靶克服，进而防止抗药性。这些研究需要结束 与项目2和3以及核心A-C在共享的技术专长、试剂/模型和 初步数据，这种合作基于10年来联合出版的记录，这些出版物有 导致对临床相关黑色素瘤生物学的深入了解，多项临床试验，甚至批准 治疗。肿瘤学和皮肤科专业知识(Ribas和Lo)和实验室与 互补方法(Ribas、Lo、Graeber)承诺加速将科学概念转化为临床试验。