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

• 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
• 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

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.

项目摘要 使用基因型定向精度疗法，包括表皮生长因子受体（EGFR）和 EGFR突变体或ALK重排非 - 小细胞肺癌（NSCLC）分别与缓解率（RR）和 与化学疗法相比，无进展生存率（PFS）。但是，PFS的改进通常是 仅计数几个月而不是数年。尽管下一代TKI的发展可以克服 具体的电阻机制，任何患者都不太可能从其晚期肺中治愈 使用顺序单药治疗的癌症。患者的重大改善很有可能 使用精确疗法的结果仅通过使用组合疗法才能发生。在电流中 提案我们通过临床试验和串行非侵入性分析整合了临床前的体外和体内研究 使用无细胞DNA的患者肿瘤进行组合疗法。我们主要关注EGFR突变体 肺癌，因为这是接受精度疗法治疗的NSCLC患者的最大子集，因为有一个 迫切需要为EGFR突变患者开发更有效的疗法。这些方法 开发组合疗法包括a。）EGFR的双重靶向，b。）垂直途径抑制（结合 EGFR抑制下游信号抑制）和c。）平行途径抑制（结合EGFR 抑制其他信号通路）。我们的策略将着重于改善EGFR抑制剂的疗法 幼稚的癌症，因此癌症在遗传上是最均匀的，并且在这里改善了治疗 方法可能会通过延迟和/或防止出现来转化为最大的临床益处 获得的耐药性。我们的临床前研究为组合临床研究提供了理由 他们的成功（或缺乏成功）和诊所的毒性将告知其他临床前方法 进一步完善治疗。通过这个迭代过程，我们的目标是对 EGFR突变体和其他肺癌患者接受基因分型定向疗法治疗的结果。