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Development of Combination Therapies to Delay/Prevent Acquired Drug Resistance

开发联合疗法以延迟/预防获得性耐药性

基本信息

批准号：
9604939
负责人：
Pasi A Janne
金额：
$ 104.75万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-10 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9604939
关键词：
Cancer Patient Clinic Clinical Clinical Research Clinical Trials Combined Modality Therapy Coupled DNA Development Drug resistance Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Genotype Goals In Vitro Malignant Neoplasms Malignant neoplasm of lung Non-Small-Cell Lung Carcinoma Oncogenic Outcome Pathway interactions Patient-Focused Outcomes Patients Plasma Precision therapeutics Process Progression-Free Survivals Receptor Inhibition Signal Pathway Signal Transduction Toxic effect Translating Tyrosine Kinase Inhibitor acquired drug resistance anaplastic lymphoma kinase base cell free DNA chemotherapy drug development effective therapy improved improved outcome in vivo mutant next generation pre-clinical preclinical study prevent resistance mechanism response success tumor

项目摘要

Project Summary The use of genotype directed precision therapies, including epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in EGFR mutant or ALK rearranged non- small cell lung cancer (NSCLC), respectively, is associated with improvements in both response rate (RR) and progression free survival (PFS) compared to chemotherapy. However, the PFS improvements are typically only counted in months rather than years. Despite the development of next generation TKIs that can overcome specific resistance mechanisms, it is very unlikely that any patient will be cured from their advanced lung cancer using sequential single agent treatment. It is more than likely that significant improvements in patient outcomes using precision therapies will only occur through the use of combination therapies. In the current proposal we integrate pre-clinical in vitro and in vivo studies, with clinical trials and serial non-invasive analyses of patient's tumors using cell free DNA to develop combination therapies. We focus primarily on EGFR mutant lung cancer as this is the largest subset of NSCLC patients treated with precision therapies and as there is a desperate need to developing more effective therapies for EGFR mutant patients. The approaches to developing combination therapies include a.) dual targeting of EGFR, b.) vertical pathway inhibition (combining EGFR inhibition with downstream signaling inhibition) and c.) parallel pathway inhibition (combining EGFR inhibition with other signaling pathways). Our strategy will focus on improving therapies for EGFR inhibitor naïve cancers, as such cancers are genetically the most homogeneous, and where improving treatment approaches will likely translates into the greatest clinical benefit by delaying and/or preventing the emergence of acquired drug resistance. Our preclinical studies provide the rationale for the combination clinical studies and their success (or lack thereof) and toxicity in the clinic will inform about additional preclinical approaches to further refine treatments. Through this iterative process, our goal is to make significant improvements in the outcome of EGFR mutant and other lung cancer patients treated with genotyped directed therapies.

项目总结