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:
    10685418
  • 负责人:
  • 金额:
    $ 35.45万
  • 依托单位:
  • 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

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/文摘:

项目成果

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会议论文数量(0)
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DOUGLAS K GRAHAM其他文献

DOUGLAS K GRAHAM的其他文献

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{{ truncateString('DOUGLAS K GRAHAM', 18)}}的其他基金

Novel TYRO3 inhibitors for treatment of cancer
用于治疗癌症的新型 TYRO3 抑制剂
  • 批准号:
    10182743
  • 财政年份:
    2021
  • 资助金额:
    $ 35.45万
  • 项目类别:
Novel TYRO3 inhibitors for treatment of cancer
用于治疗癌症的新型 TYRO3 抑制剂
  • 批准号:
    10582629
  • 财政年份:
    2021
  • 资助金额:
    $ 35.45万
  • 项目类别:
Novel TYRO3 inhibitors for treatment of cancer
用于治疗癌症的新型 TYRO3 抑制剂
  • 批准号:
    10381542
  • 财政年份:
    2021
  • 资助金额:
    $ 35.45万
  • 项目类别:
MERTK/AXL dual inhibitors provide novel treatment for cancer by targeting tumor cells and activating anti-tumor immunity
MERTK/AXL双重抑制剂通过靶向肿瘤细胞并激活抗肿瘤免疫为癌症提供新的治疗方法
  • 批准号:
    10373031
  • 财政年份:
    2020
  • 资助金额:
    $ 35.45万
  • 项目类别:
MERTK/AXL dual inhibitors provide novel treatment for cancer by targeting tumor cells and activating anti-tumor immunity
MERTK/AXL双重抑制剂通过靶向肿瘤细胞并激活抗肿瘤免疫为癌症提供新的治疗方法
  • 批准号:
    10589107
  • 财政年份:
    2020
  • 资助金额:
    $ 35.45万
  • 项目类别:
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:
    10210199
  • 财政年份:
    2019
  • 资助金额:
    $ 35.45万
  • 项目类别:
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:
    10459441
  • 财政年份:
    2019
  • 资助金额:
    $ 35.45万
  • 项目类别:
Novel Biologically Targeted Therapy Against the Mer and Axl Receptor Tyrosine Kin
针对 Mer 和 Axl 受体酪氨酸激酶的新型生物靶向疗法
  • 批准号:
    8118019
  • 财政年份:
    2010
  • 资助金额:
    $ 35.45万
  • 项目类别:
Novel Biologically Targeted Therapy Against the Mer and Axl Receptor Tyrosine Kin
针对 Mer 和 Axl 受体酪氨酸激酶的新型生物靶向疗法
  • 批准号:
    8267692
  • 财政年份:
    2010
  • 资助金额:
    $ 35.45万
  • 项目类别:
Novel Biologically Targeted Therapy Against the Mer and Axl Receptor Tyrosine Kin
针对 Mer 和 Axl 受体酪氨酸激酶的新型生物靶向疗法
  • 批准号:
    7992763
  • 财政年份:
    2010
  • 资助金额:
    $ 35.45万
  • 项目类别:

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