Development of Combination Therapies to Delay/Prevent Acquired Drug Resistance

项目摘要 使用基因型导向的精确治疗，包括表皮生长因子受体（EGFR）和 EGFR突变体或ALK重排非间变性淋巴瘤激酶（ALK）酪氨酸激酶抑制剂（TKI） 小细胞肺癌（NSCLC）分别与缓解率（RR）和 无进展生存期（PFS）。然而，PFS改进通常 只以月而不是年计算。尽管下一代TKI的发展可以克服 由于存在特定的耐药机制，因此任何患者都不太可能从其晚期肺部治愈。 使用顺序单一药剂治疗的癌症。很可能患者的显著改善 使用精确疗法的结果只能通过使用联合疗法来实现。在当前 我们建议将临床前体外和体内研究与临床试验和系列非侵入性分析整合起来 使用无细胞DNA来开发联合疗法。我们主要关注EGFR突变体 肺癌，因为这是接受精确治疗的NSCLC患者的最大子集， 迫切需要为EGFR突变患者开发更有效的治疗方法。的途径 开发联合疗法包括a.）EGFR的双重靶向，B.）垂直通路抑制（结合 具有下游信号传导抑制的EGFR抑制）和c.）平行途径抑制（结合EGFR 与其他信号通路的抑制）。我们的策略将集中于改善EGFR抑制剂的治疗 初治癌症，因为这种癌症在遗传上是最同质的， 通过延迟和/或预防这些疾病的发生， 获得性抗药性的证据我们的临床前研究为联合临床研究提供了依据 以及它们在临床上的成功（或失败）和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，我们的目标是在 EGFR突变体和其他肺癌患者接受基因分型定向治疗的结果。

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.