Project 1 - Integrating targeted and immune therapies for BRAF mutant colorectal cancer

项目1 - BRAF突变结直肠癌的靶向治疗和免疫治疗相结合

基本信息

批准号：
10670779
负责人：
Ryan Bruce Corcoran
金额：
$ 31.39万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10670779
关键词：
Affect BRAF gene Biopsy CD8-Positive T-Lymphocytes Cancer Center Clinic Clinical Clinical Data Clinical Trials Collaborations Collection Colorectal Cancer Combined Modality Therapy Conduct Clinical Trials Correlative Study Coupled DNA Sequence Alteration Data Disease Epidermal Growth Factor Receptor Feedback Flow Cytometry Future Gene Expression Profiling Grant Histologic Immune Immune Targeting Immune response Immunocompetent Immunofluorescence Immunologic Immunologics Immunotherapy Isogenic transplantation Knowledge MAP Kinase Gene MEK inhibition MEKs Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Mediator Microsatellite Instability Microsatellite Repeats Modeling Molecular Mutation Pathology Pathway interactions Patients Population Prognosis Resistance Series Signal Transduction T-Lymphocyte Testing Therapeutic Translating Tumor Immunity Tumor-infiltrating immune cells anti-PD-1 clinical efficacy design effectiveness evaluation exome sequencing immune cell infiltrate immune checkpoint blockade immunogenic immunogenicity improved inhibitor innovation insight melanoma molecular subtypes mouse model mutant neoplastic cell next generation novel novel therapeutics pharmacologic pre-clinical preclinical study programmed cell death protein 1 resistance mechanism response single-cell RNA sequencing synergism targeted treatment therapeutic development transcriptome sequencing transcriptomics tumor tumor progression

项目摘要

Project Summary BRAF inhibitors lack efficacy in BRAF mutant (BRAFm) CRC (response rate only 5%) in contrast to response rates of >50% in BRAFm melanoma. Key studies conducted as part of our prior SPORE project identified feedback networks present in CRC (but absent in melanoma) that lead to rapid reactivation of MAPK signaling following BRAF inhibition, as primary drivers of resistance. This critical discovery led to clinical trials of BRAFi-based therapeutic combinations designed to block MAPK reactivation, resulting in an increased response rate for BRAFm CRC patients from 5% to >30%. Despite these therapeutic advances, clinical benefit is not durable, with a median PFS of only 4-5 months. Here we will explore potential cooperativity between targeted MAPK inhibition (MAPKi) and immune checkpoint blockade (ICB) to convert less immune responsive tumors to more immunogenic tumors. BRAFm CRC represents a prime population for exploring potential cooperativity, as 20-30% of metastatic BRAFm CRCs harbor MSI, which confers responsiveness to ICB. Moreover, we have observed durable responses of >5 years in MSI BRAFm CRC patients receiving MAPKi alone. In MSS BRAFm CRC patients, we see marked induction of CD4+ and CD8+ T-cells with MAPKi alone in paired tumor biopsies, and our preclinical mouse models demonstrate a cooperative effect of MAPKi and PD-1 IC in MSS BRAFm CRC. We propose a comprehensive effort using innovative immune competent BRAFm CRC mouse models, cutting-edge molecular and immune analyses of paired pre- and on-treatment tumor biopsies, and novel clinical trials to explore combined MAPKi and ICB as a strategy to achieve durable benefit in BRAFm CRC patients. Aim 1 will define the effects of MAPKi alone and with PD-1 ICB on immunogenicity of BRAFm CRC and anti-tumor immunity using immunologic and transcriptional profiling approaches to analyze novel BRAFm CRC models and a unique collection of paired pre-treatment and on-treatment biopsies from BRAFm CRC patients given BRAF/EGFR/MEKi. Aim 2 will conduct clinical trials and correlative studies of novel immune and targeted combinations for BRAFm CRC, evaluating clinical efficacy of combined BRAF/MEK/PD-1 inhibition. We will collaborate with the Pathology Core for multiplexed immune analysis of tumor biopsies, and the Biostats Core for analysis of bulk and single cell RNAseq and whole-exome sequencing. These studies will provide key insights to guide design of future trials. Aim 3 will define mechanisms of response and resistance to combined MAPKi and ICB in BRAFm CRC mouse models, and test strategies to overcome resistance to MAPKi/anti-PD-1 using combined ICB and modulators of immunosuppressive mechanisms defined by our analyses in Aims 1 and 2. These studies will define the potential synergy between MAPKi and ICB in BRAFm CRC and mechanisms of response and resistance to establish a new therapeutic paradigm for this lethal CRC subtype

项目摘要 BRAF抑制剂缺乏BRAF突变体（BRAFM）CRC（仅5％）的功效 BRAFM黑色素瘤的反应率> 50％。作为我们先前的孢子项目的一部分进行的关键研究确定了CRC中存在的反馈网络（但在黑色素瘤中不存在），这些反馈网络导致快速重新激活 BRAF抑制后的MAPK信号传导是电阻的主要驱动因素。这个批判发现导致基于BRAFI的治疗组合的临床试验，旨在阻止MAPK重新激活，导致 BRAFM CRC患者的应答率从5％到> 30％。尽管有这些治疗性进步，临床益处不持久，中位PFS仅为4-5个月。在这里我们将探索靶向MAPK抑制（MAPKI）和免疫检查点封锁之间的潜在合作性（ICB）将较小的免疫反应性肿瘤转化为更多的免疫原性肿瘤。 BRAFM CRC代表探索潜在合作的主要人口，因为20-30％的转移性BRAFM CRCS港口 MSI，赋予对ICB的响应能力。此外，我们观察到持久的响应> 5年在MSI BRAFM CRC患者中，仅接受MAPKKI。在MSS BRAFM CRC患者中，我们看到在配对的肿瘤活检中，单独使用MAPKI的CD4+和CD8+ T细胞诱导，我们的临床前小鼠模型在MSS BRAFM CRC中证明了MAPKI和PD-1 IC的合作效应。我们提出了使用创新的免疫胜任BRAFM CRC鼠标模型的全面努力，对配对前和治疗肿瘤活检的尖端分子和免疫分析以及新颖的临床试验以探索MAPKI和ICB的合并作为实现BRAFM持久收益的策略 CRC患者。 AIM 1将单独定义MAPKI和PD-1 ICB对免疫原性的影响 BRAFM CRC和抗肿瘤免疫，采用免疫和转录分析方法分析新颖的BRAFM CRC模型以及独特的配对预处理和处理 BRAFM CRC患者的活检给予了BRAF/EGFR/MEKI。 AIM 2将进行临床试验，并 BRAFM CRC的新型免疫和靶向组合的相关研究，评估临床联合BRAF/MEK/PD-1抑制的功效。我们将与病理核心合作肿瘤活检的多重免疫分析以及用于分析和单细胞分析的生物稳定核心 RNASEQ和全外观测序。这些研究将为指导未来设计提供关键见解试验。 AIM 3将定义BRAFM中对MAPKI和ICB组合的响应和抵抗的机制 CRC小鼠模型以及使用联合ICB克服对MAPKI/抗PD-1的抵抗力的测试策略以及我们在目标1和2中的分析定义的免疫抑制机制的调节因子。研究将定义BRAFM CRC中MAPKI和ICB之间的潜在协同作用以及为这种致命的CRC亚型建立新的治疗范式的反应和抵抗力