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: 10469501
• 负责人: Pasi A Janne
• 金额: $ 102.66万
• 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/10469501
• 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.

项目概要 使用基因型定向精准疗法，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 (TKI) 在 EGFR 突变或 ALK 重排非 小细胞肺癌 (NSCLC) 分别与缓解率 (RR) 和缓解率 (RR) 的改善相关 与化疗相比，无进展生存期（PFS）。然而，PFS 的改善通常是 只以月计算，而不以年计算。尽管下一代 TKI 的开发可以克服 由于特定的抵抗机制，任何晚期肺病患者都不太可能被治愈 使用序贯单药治疗的癌症。患者的病情很可能会得到显着改善 精准疗法的结果只有通过联合疗法才能实现。在当前 建议我们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相结合 使用无细胞DNA对患者的肿瘤进行研究以开发联合疗法。我们主要关注 EGFR 突变体 肺癌，因为这是接受精准治疗的 NSCLC 患者中最大的一个子集，而且有 迫切需要为 EGFR 突变患者开发更有效的疗法。的方法 开发联合疗法包括 a.) EGFR 双重靶向，b.) 垂直通路抑制（结合 EGFR 抑制与下游信号传导抑制）和 c.）平行途径抑制（结合 EGFR 与其他信号通路的抑制作用）。我们的战略将专注于改善 EGFR 抑制剂的治疗 幼稚癌症，因为此类癌症在遗传上是最同质的，并且改善治疗 通过延迟和/或防止出现，方法可能会转化为最大的临床效益 的获得性耐药性。我们的临床前研究为联合临床研究提供了理论依据 它们在临床上的成功（或缺乏）和毒性将为其他临床前方法提供信息 进一步细化治疗。通过这个迭代过程，我们的目标是在以下方面做出重大改进： EGFR 突变体和其他接受基因分型定向疗法治疗的肺癌患者的结果。