Project 2: Targeting MERTK to improve outcomes for EGFR-mutated NSCLC

项目 2：靶向 MERTK 改善 EGFR 突变 NSCLC 的预后

基本信息

批准号：
10459441
负责人：
DOUGLAS K GRAHAM
金额：
$ 37.77万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-10 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10459441
关键词：
ABCG2 gene Address Aftercare Animal Model Binding Biological Markers Biopsy Biopsy Specimen Blood Blood specimen Bone Marrow Cancer Etiology Cancer Model Cancer Patient Caring Cell Culture Techniques Cell Line Cells Cessation of life Clinical Clinical Research Clinical Trials Collection Correlative Study Cytotoxic Chemotherapy Data Development Dose EGFR inhibition Enrollment Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor FDA approved Family Generations Genetic Guidelines Human Immune Immune response Immune system Immunologic Markers Immunosuppression Implant Innate Immune Response International Knock-out Knockout Mice Lead Ligands Lung MERTK gene Malignant Neoplasms Malignant neoplasm of lung Mediating Mediator of activation protein Modeling Monitor Multicenter Studies Mus Mutate Mutation National Comprehensive Cancer Network Natural Immunity Neoplasm Metastasis Newly Diagnosed Non-Small-Cell Lung Carcinoma Oncogenic Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacodynamics Phase Phase Ib Clinical Trial Phenotype Phosphorylation Prognosis Quality of life Receptor Protein-Tyrosine Kinases Recombinants Research Personnel Resistance Resistance development Role Safety Sampling Signal Transduction Testing Therapeutic Therapeutic Effect Translating Tumor Immunity Tumor-associated macrophages Tumor-infiltrating immune cells Tyrosine Kinase Inhibitor Universities cell killing chemokine clinical application cohort cytokine cytotoxic first-in-human immune function improved improved outcome inhibitor inhibitor therapy kinase inhibitor lung cancer cell mouse model mutant mutational status neoplastic cell novel novel strategies patient derived xenograft model patient response pharmacodynamic biomarker potential biomarker pre-clinical preclinical study resistance mechanism resistance mutation response biomarker small hairpin RNA subcutaneous targeted treatment therapeutic target tumor tumor growth tumor microenvironment tumorigenesis

项目摘要

Summary/Abstract: Lung cancer is the most common cancer worldwide and the leading cause of cancer-related death in the US. EGFR tyrosine kinase inhibitors (TKIs) have improved outcomes for patients who have non-small cell lung cancer (NSCLC) with an activating EGFR mutation (EGFRMT), but many tumors do not respond and most that do will become resistant in 9-12 months. Osimertinib, a 3rd generation EGFR TKI, has recently advanced to frontline therapy for EGFRMT NSCLC, irrespective of T790M mutation, but treatment options remain limited for patients who develop resistant tumors. This proposal describes preclinical studies to evaluate inhibition of the MERTK receptor tyrosine kinase in combination with EGFR TKIs for treatment of EGFRMT NSCLC and includes a phase 1b clinical trial to test the combination in these patients. 70% of NSCLCs have abnormally high levels of MERTK and inhibition in tumor cells decreases tumor growth in mice. MERTK is also present in immune cells in the tumor microenvironment, where it suppresses the anti-tumor innate immune response. Our data suggest that inhibition of MERTK reprograms the immune system to attack the tumor. MERTK can also mediate resistance to EGFR TKIs, including osimertinib, suggesting that MERTK inhibition will sensitize EGFRMT tumors to treatment with EGFR TKIs and may decrease development of resistance. These data identify MERTK as a new target in NSCLC and implicate MERTK-targeted inhibitors as an unprecedented opportunity to provide a three-pronged therapeutic approach in a single drug, leading to (1) direct tumor cell killing, (2) activation of anti-tumor innate immunity, and (3) increased sensitivity to EGFR TKI therapy. To test this idea and generate drugs that can be used in humans, we developed MERTK-selective TKIs, including MRX-2843. MRX-2843 is effective as monotherapy in mice and increases sensitivity to EGFR TKIs in EGFRMT NSCLC cells. The proposed studies use MRX-2843 and other MERTK inhibitors to investigate the effects of combined MERTK and EGFR inhibition in cell culture and mouse models of EGFRMT NSCLC, including models with tumor cells implanted directly in the lung, models derived from fresh patient samples, and models of tumor cell metastasis. Mice with mertk knock- out will also be used to determine the effects of MERTK inhibition in the tumor microenvironment and its impact on anti-tumor immunity. Additional studies will determine how MERTK inhibition in the immune system leads to tumor rejection. Finally, a highlight of this project is the dedicated clinical trial of MRX-2843 and osimertinib in patients with advanced EGFRMT NSCLC, a study that includes 2 expansion cohorts with paired collection of pre- and post-treatment tumor biopsies and blood samples to evaluate biomarkers of MERTK inhibition, including changes in immune function, following treatment with MRX-2843. The results from the clinical trial and associated studies will provide more effective and less toxic treatment options leading to optimized care and improved survival for patients with EGFRMT NSCLC.

摘要/摘要：肺癌是全世界最常见的癌症，也是美国癌症相关死亡的主要原因。 EGFR 酪氨酸激酶抑制剂 (TKI) 改善了非小细胞肺癌患者的预后 (NSCLC) 具有激活 EGFR 突变 (EGFRMT)，但许多肿瘤不会产生反应，而且大多数会产生反应 9-12个月内产生耐药性。奥希替尼（Osimertinib）是第三代EGFR TKI，最近已进入一线治疗 EGFRMT NSCLC 的治疗，无论 T790M 突变如何，但患者的治疗选择仍然有限产生耐药肿瘤的人。该提案描述了评估 MERTK 抑制作用的临床前研究受体酪氨酸激酶与 EGFR TKI 联合治疗 EGFRMT NSCLC，包括一个阶段 1b 临床试验在这些患者中测试该组合。 70% 的 NSCLC 具有异常高水平的 MERTK 抑制肿瘤细胞可降低小鼠肿瘤的生长。 MERTK 也存在于肿瘤的免疫细胞中微环境，它抑制抗肿瘤先天免疫反应。我们的数据表明抑制 MERTK 重新编程免疫系统以攻击肿瘤。 MERTK还可以介导EGFR耐药 TKI，包括奥西替尼，表明 MERTK 抑制将使 EGFRMT 肿瘤对治疗敏感 EGFR TKI 可能会减少耐药性的产生。这些数据将 MERTK 确定为 NSCLC 的新靶点并暗示 MERTK 靶向抑制剂是提供三管齐下的前所未有的机会单一药物的治疗方法，导致（1）直接杀死肿瘤细胞，（2）激活抗肿瘤先天性 (3) 提高对 EGFR TKI 治疗的敏感性。为了测试这个想法并生产可以用于人类时，我们开发了 MERTK 选择性 TKI，包括 MRX-2843。 MRX-2843 的功效为在小鼠中进行单一疗法，并增加 EGFRMT NSCLC 细胞对 EGFR TKI 的敏感性。拟议的研究使用MRX-2843和其他MERTK抑制剂研究MERTK和EGFR联合抑制的效果在 EGFRMT NSCLC 的细胞培养和小鼠模型中，包括将肿瘤细胞直接植入到肺、源自新鲜患者样本的模型以及肿瘤细胞转移模型。具有 mertk 敲击的小鼠 out 还将用于确定 MERTK 抑制对肿瘤微环境的影响及其影响关于抗肿瘤免疫。其他研究将确定免疫系统中 MERTK 抑制如何导致肿瘤排斥。最后，该项目的一大亮点是MRX-2843和奥希替尼的专门临床试验晚期 EGFRMT NSCLC 患者，这项研究包括 2 个扩展队列，其中包含配对收集的预以及治疗后肿瘤活检和血液样本，以评估 MERTK 抑制的生物标志物，包括 MRX-2843 治疗后免疫功能发生变化。临床试验结果和相关研究将提供更有效、毒性更小的治疗方案，从而优化护理和 EGFRMT NSCLC 患者的生存率得到改善。