Overcoming Resistance to Anti-EGFR Therapy by Drug Repurposing

通过药物再利用克服抗 EGFR 治疗的耐药性

基本信息

批准号：
9319655
负责人：
BINGLIANG FANG
金额：
$ 51.41万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9319655
关键词：
Address Aftercare Agammaglobulinaemia tyrosine kinase Animal Model Apoptosis Auranofin B lymphoid malignancy Biopsy Bypass Cancer Patient Cancer cell line Cells Chronic Lymphocytic Leukemia Clinic Clinical Clinical Research Clinical Treatment Clinical Trials Combined Modality Therapy Data Diarrhea Drug resistance ERBB2 gene Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib Exanthema FDA approved Gefitinib Genetically Engineered Mouse Goals Growth In Vitro Investigation Knowledge Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of thyroid Mantle Cell Lymphoma Mutation Non-Small-Cell Lung Carcinoma Outcome PI3K/AKT PTEN gene Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Phase Pre-Clinical Model Progression-Free Survivals Public Health Quality of life Regimen Reporting Research Resistance Resistance development Rheumatoid Arthritis STAT3 gene Sampling Signal Transduction Specimen Testing Toxic effect Translating Treatment Efficacy Tyrosine Kinase Inhibitor Vertebral column anticancer activity axl receptor tyrosine kinase base cancer cell clinical application clinical translation clinically relevant efficacy testing epithelial to mesenchymal transition improved improved outcome in vivo inhibitor/antagonist innovation mouse model mutant novel novel therapeutics overexpression pre-clinical public health relevance receptor resistance mechanism response targeted treatment thioredoxin reductase tumor

项目摘要

DESCRIPTION (provided by applicant): Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as gefitinib, erlotinib, and afatinib have dramatically improved outcomes in non-small cell lung cancer (NSCLC) patients with EGFR mutations. Unfortunately, acquired resistance develops after a median of 10-13 months and treatment toxicities (acneiform rash, diarrhea) can limit combination approaches to restore the sensitivity. The most commonly clinically observed mechanism of EGFR TKI resistance is the T790M mutation, found in 40-50% of erlotinib- or gefitinib- resistant tumors. Other T790M-independent resistance mechanisms include bypass of EGFR via HER-2 or MET, STAT3 or NF-¿B activation, or epithelial-to-mesenchymal-transition (EMT)-associated AXL signaling. There are no approved agents effective against EGFR with a T790M mutation. Developing effective and tolerable regimens for overcoming EGFR TKI resistance remains an important unmet need. Our preliminary studies have shown that ibrutinib, an inhibitor of Bruton's tyrosine kinase recently FDA approved for several B-cell malignancies, functions as an inhibitor of mutant EGFR and induces anticancer activity in EGFR-mutant NSCLC cells, including erlotinib-resistant cells harboring a T790M mutation, and also inhibits HER-2 signaling. This unexpected finding led us to develop a clinical trial to treat EGFR-mutant NSCLC with ibrutinib, which will begin accrual early next year. Moreover, ibrutinib was recently reported to be well tolerated in combination with other targeted therapeutics. These results provide proof-of-principle evidence of the feasibility of overcoming resistance to anti- EGFR therapy by repurposing FDA-approved drugs. Based on our preliminary data, we hypothesize that ibrutinib represents a novel EGFR inhibitor that may overcome TKI resistance through its activity against EGFR T790M and HER2, and through its combination with other targeted therapeutics. Because of ibrutinib's activity and favorable toxicity profile, it may be a useful backbone for combination regimens that simultaneously target multiple resistance mechanisms. Nevertheless, significant knowledge gaps remain regarding the activity of ibrutinib and optimal combination regimens to overcome resistance. To address these gaps we propose the following Specific Aims: 1) Determine the direct effect of ibrutinib on clinically relevant mutations in preclinical models, including T790M mutations and HER2 overexpressions; 2) Characterize the mechanisms of T790M- independent resistance to ibrutinib in preclinical models, and develop more effective combination regimens including those with STAT3/NF-¿B and AXL inhibitors; and 3) Test the efficacy of ibrutinib in EGFR-mutant NSCLC patients and, using specimens from this trial, investigate the determinants of ibrutinib response and resistance. This proposal has significant public health implications because overcoming EGFR TKI resistance will have a significant impact on clinical outcomes and quality of life of EGFR-mutant NSCLC patients; furthermore, by repurposing agents already in routine clinical use, it is poised for rapid clinical translation.

描述：表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKIS），例如Gefitinib和Tinib，在具有EGFR突变的中位数后，在非小细胞肺癌（NSCLC）患者的非小细胞肺癌（NSCLC）患者中急剧改善了结果。和治疗毒性NSITIVE。 b激活或间充质转换（EMT）相关的AXL信号传导。 Itor of Mutant EGFR and Inducancer Activity in EGFR-Mutant NSCLC CELLS, Including Erlotinib-Resistant Cells Harboring A T790m Mutation, And ALSO INHIBITS HER-2 SIS UNEXPECTED Finding Led Us to Develop A Clinical Trial To Trial to Tor-Mutant NSCLC with IBRUTINIB CCRUAL明年。 EGFR抑制剂的活性。克服。我们提出了以下特定目的：1）ibrutinib在临床模型中的临床再生能力的直接效果，包括T790M突变和HER2过表达； 2）和开发有效的组合方案，包括具有STAT3/NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF NF NF NF NF NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF-NF，以及B和AXL抑制剂的抑制作用和抗性具有重大的公共卫生意义，因为克服EGFR TKI耐药性将对EGFR-MUTHING NSCLC患者的临床效果产生重大影响。快速临床翻译。