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

项目概要与 BRAF 突变 (BRAFm) CRC 相比，BRAF 抑制剂缺乏疗效（缓解率仅为 5%） BRAFm 黑色素瘤的缓解率 >50%。作为我们之前 SPORE 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（但黑色素瘤中不存在），该网络导致快速重新激活 BRAF 抑制后的 MAPK 信号传导是耐药性的主要驱动因素。这一重要发现导致基于 BRAFi 的治疗组合的临床试验旨在阻止 MAPK 重新激活，从而导致 BRAFm CRC 患者的缓解率从 5% 提高到 >30%。尽管有这些治疗但临床获益并不持久，中位 PFS 仅为 4-5 个月。在这里我们将探索靶向 MAPK 抑制 (MAPKi) 与免疫检查点阻断之间的潜在协同作用（ICB）将免疫反应性较低的肿瘤转化为免疫原性较高的肿瘤。 BRAFm CRC 代表探索潜在合作性的主要人群，因为 20-30% 的转移性 BRAFm CRC 存在 MSI，赋予对 ICB 的响应能力。此外，我们观察到超过 5 年的持久反应在仅接受 MAPKi 治疗的 MSI BRAFm CRC 患者中。在 MSS BRAFm CRC 患者中，我们看到明显的在配对肿瘤活检中单独使用 MAPKi 诱导 CD4+ 和 CD8+ T 细胞，以及我们的临床前研究小鼠模型证明了 MAPKi 和 PD-1 IC 在 MSS BRAFm CRC 中的协同作用。我们提出使用创新的免疫能力 BRAFm CRC 小鼠模型进行全面的努力，配对治疗前和治疗中肿瘤活检的尖端分子和免疫分析，以及新颖的探索 MAPKi 和 ICB 联合治疗作为 BRAFm 持久获益策略的临床试验结直肠癌患者。目标 1 将定义单独使用 MAPKi 以及与 PD-1 ICB 联合使用对免疫原性的影响使用免疫学和转录分析方法的 BRAFm CRC 和抗肿瘤免疫分析新型 BRAFm CRC 模型以及配对治疗前和治疗中的独特集合对接受 BRAF/EGFR/MEKi 治疗的 BRAFm CRC 患者进行活检。目标2将进行临床试验并 BRAFm CRC 新型免疫和靶向组合的相关研究，评估临床 BRAF/MEK/PD-1 联合抑制的功效。我们将与病理学核心合作肿瘤活检的多重免疫分析，以及用于分析批量和单细胞的 Biostats Core RNAseq 和全外显子组测序。这些研究将为指导未来的设计提供重要见解试验。目标 3 将定义 BRAFm 中对 MAPKi 和 ICB 组合的反应和抵抗机制 CRC 小鼠模型，以及使用组合 ICB 克服 MAPKi/抗 PD-1 耐药性的测试策略以及我们在目标 1 和 2 中的分析所定义的免疫抑制机制的调节剂。这些研究将确定 MAPKi 和 ICB 在 BRAFm CRC 中的潜在协同作用及其机制反应和耐药，为这种致命的 CRC 亚型建立新的治疗模式