Development of Combination Therapies to Delay/Prevent Acquired Drug Resistance

项目摘要 使用针对基因的精确治疗，包括表皮生长因子受体(EGFR)和 间变性淋巴瘤激酶(ALK)酪氨酸激酶抑制剂(TKIs)在EGFR突变型或ALK重排的非突变型 小细胞肺癌(NSCLC)分别与反应率(RR)和 与化疗相比，无进展生存(PFS)。然而，PFS的改进通常是 只按月计算，而不是按年计算。尽管下一代TKI的发展可以克服 特定的耐药机制，任何患者都不太可能从晚期肺中治愈 使用单剂序贯疗法治疗癌症。很有可能患者的显著改善 使用精确疗法的结果只会通过联合疗法的使用而发生。在当前 建议我们将临床前的体外和体内研究与临床试验和系列非侵入性分析相结合 使用无细胞DNA来开发联合疗法。我们主要关注的是EGFR突变 肺癌，因为这是接受精确治疗的非小细胞肺癌患者中最大的一组，而且有 迫切需要为EGFR突变患者开发更有效的治疗方法。解决问题的方法 开发联合疗法包括一种。)EGFR的双重靶向，b.)垂直通路抑制(合并 EGFR抑制和下游信号抑制)和c.)平行通路抑制(结合EGFR 与其他信号通路的抑制)。我们的战略将集中在改进EGFR抑制剂的治疗上 幼稚癌症，因为这种癌症在基因上是最同质性的，并且改善了治疗 治疗方法可能会通过延迟和/或预防这种情况的出现而转化为最大的临床益处。 获得性抗药性。我们的临床前研究为联合临床研究提供了理论基础 它们的成功(或缺乏)和在临床上的毒性将为其他临床前治疗方法提供信息 进一步细化处理。通过这个迭代过程，我们的目标是在 EGFR突变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.