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: 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
• 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

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 靶向突变的小分子抑制剂和免疫检查点阻滞或ICB（抗PD-1和-CTLA-4） 抗体）已扩大了晚期BRAFMUT黑色素瘤患者的寿命质量和数量。超过 ICB在多达60％的患者中无效，晚期NRASMUT黑色素瘤患者没有标准 护理选项。由于阻力的快速发作，MEK抑制剂（MEKI）单一疗法的临床有限 针对Nrasmut黑色素瘤的活性，除了先前暴露于ICB的黑色素瘤外，潜在的活性 （Nemo试验）。在这里，我们建议设计基于MEKI的组合序列方案针对高级 Nrasmut黑色素瘤。首先，我们将测试通过抗PD-1/L1启动MEKI响应能力的概念 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机制 人类受试者的作用和先天/获得的抵抗（通过进行II期研究者发起的试验） 以及合成性黑色素瘤模型。第二，我们将测试结合下一代RAF的概念 抑制剂（rafi）带有MEKI以克服并防止MEKI抗性。这些研究将在 人黑色素瘤细胞系，患者衍生的异种移植物（PDXS）和合成模型。第三，我们将测试 通过在药理学上利用标志性的抗性脆弱性来克服MEKI抵抗的概念 肿瘤：Meki戒断引起的MEKI添加或肿瘤细胞死亡。具体来说，诱导回归 在各种耐Nrasmut Meki耐药的PDX模型中，我们将测试一种涉及测序的策略 MEKI到多ADP核糖聚合酶抑制剂（PARPI）或涉及MEKI之间旋转的另一种策略 和parpi。我们还将通过诱导各种范围来测试这些测序/旋转策略是否 免疫原性的细胞死亡和/或先天免疫将使Nrasmut黑色素瘤敏感到抗PD-1/L1 治疗。在这些临床和临床前研究中，我们将得出多词数据并评估候选途径 识别预测性生物标志物。除了基于大肿瘤的多词分析（外显子，基因组， 纵向肿瘤样品的转录组，甲基化，染色质可及性，蛋白质组，TCR锁骨型） 我们还将剖析Nrasmut黑色素瘤的单细胞（SCRNA-SEQ，CYTOF）进化 组合序列的目标以克服然后防止抗性。这些研究需要接近 与项目2和3和核心A-C合作，在共享的技术专长，试剂/模型和 初步数据，这项合作基于共同出版物的10年记录 导致对临床相关的黑色素瘤生物学，多个临床试验的深刻见解，甚至批准 疗法。肿瘤学和皮肤病学专业知识（RIBAS和LO）以及实验室与实验室的结合与 互补方法（Ribas，Lo，Graeber）有望将科学概念加速到临床测试。