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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：
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
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/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

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