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

• 批准号: 10685418
• 负责人: DOUGLAS K GRAHAM
• 金额: $ 35.45万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 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/10685418
• 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; Dedications; 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; Ligands; Lung; MERTK gene; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mediator; Modeling; Monitor; Multicenter Studies; Mus; Mutate; Mutation; National Comprehensive Cancer Network; Natural Immunity; Neoplasm Metastasis; New Agents; 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; Recommendation; Research Personnel; Resistance; Resistance development; Role; Safety; Sampling; Signal Transduction; Testing; Therapeutic; Therapeutic Effect; Translating; Tumor Immunity; Tumor-associated macrophages; Tyrosine Kinase Inhibitor; Universities; cell killing; chemokine; clinical application; cohort; cytokine; cytotoxic; first-in-human; immune cell infiltrate; 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; permissiveness; pharmacodynamic biomarker; potential biomarker; pre-clinical; preclinical study; programs; resistance mechanism; resistance mutation; response biomarker; small hairpin RNA; subcutaneous; targeted treatment; therapeutic target; tumor; tumor growth; tumor microenvironment; tumorigenesis

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/文摘: