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: 10443859
• 负责人: ROGER S LO
• 金额: $ 50.76万
• 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/10443859
• 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; 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

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，本次合作基于 10 年的联合出版物记录 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。