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/摘要： 肺癌是全球最常见的癌症，也是美国与癌症相关死亡的主要原因。 EGFR酪氨酸激酶抑制剂（TKI）的患者改善了患有非小细胞肺癌的患者的结局 （NSCLC）具有激活的EGFR突变（EGFRMT），但许多肿瘤没有反应，大多数肿瘤都会 在9-12个月内变得抗药性。 Osimertinib是第三代EGFR TKI，最近晋升为前线 EGFRMT NSCLC的治疗，无论T790M突变如何，但患者的治疗选择仍然有限 患有抗性肿瘤的人。该提案描述了评估MERTK抑制的临床前研究 受体酪氨酸激酶与EGFR TKI结合用于治疗EGFRMT NSCLC，并包括一个相 1B临床试验测试这些患者的组合。 70％的NSCLC具有异常高的MERTK 肿瘤细胞的抑制作用可降低小鼠的肿瘤生长。 MERTK也存在于肿瘤中的免疫细胞中 微环境，它抑制了抗肿瘤的先天免疫反应。我们的数据表明抑制作用 MERTK的重新编程以攻击肿瘤。 MERTK还可以介导对EGFR的抗性 TKI，包括osimertinib，表明MERTK抑制作用将使EGFRMT肿瘤敏感 EGFR TKI，可能会降低电阻的发展。这些数据将MERTK识别为NSCLC中的新目标 并暗示将MERTK靶向的抑制作用是前所未有的机会 单一药物的治疗方法，导致（1）直接肿瘤细胞杀死，（2）抗肿瘤先天的激活 免疫力和（3）对EGFR TKI治疗的敏感性提高。测试这个想法并产生可以是的药物 我们在人类中使用了MERTK选择性TKI，包括MRX-2843。 MRX-2843是有效的 小鼠单一疗法，并增加对EGFRMT NSCLC细胞中EGFR TKI的敏感性。提出的研究 使用MRX-2843和其他MERTK抑制剂研究组合MERTK和EGFR抑制的影响 在EGFRMT NSCLC的细胞培养和小鼠模型中，包括直接植入肿瘤细胞的模型 肺，源自新鲜患者样品的模型和肿瘤细胞转移的模型。 MICE用Mertk敲门 OUT还将用于确定MERTK抑制在肿瘤微环境中的影响及其影响 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，该项目的亮点是MRX-2843和Osimertinib的专用临床试验 患有晚期EGFRMT NSCLC的患者，一项研究包括2个扩展队列 以及治疗后的肿瘤活检和血液样本，以评估MERTK抑制的生物标志物，包括 通过MRX-2843处理后，免疫功能的变化。临床试验的结果和 相关研究将提供更有效和毒性较小的治疗选择，从而提供优化的护理和 EGFRMT NSCLC患者的生存率提高。