Personalizing NSCLC Therapy: Exploiting KRAS activated pathways

描述（由申请人提供）：肺癌是全球癌症相关死亡的主要原因，转移性NSCLC患者的预后仍然很差，5年生存率低于16%。我们的团队进行了第一个完成的生物标志物驱动的临床项目，名为肺癌消除靶向治疗的生物标志物整合方法（BATTLE-1），其中纳入了治疗NSCLC的个性化药物方法;然而，对新靶向NSCLC治疗的耐药性仍然是一个尚未解决的医学挑战。KRAS在高达30%的NSCLC病例中发生突变，并激活多种信号传导途径，从而消除许多正在开发的NSCLC靶向药物的作用;因此，解决突变KRAS仍然是NSCLC治疗的主要未满足需求。我们计划通过我们的前瞻性、适应性随机试验“BATTLE- 2项目：一项在既往接受过治疗的晚期非小细胞肺癌患者中进行的生物标志物整合靶向治疗研究”（BATTLE-2）来研究KRAS信号传导机制及其对下游信号通路抑制剂应答的影响。我们将以从BATTLE-1获得的知识为基础，包括初步发现特定类型的KRAS突变可能与临床结果相关。在BATTLE- 2中，难治性NSCLC患者将接受强制性新鲜活检，并在肿瘤分子分析的指导下，适应性随机分配至EGFR（厄洛替尼）或RAF/VEGFR 2/PDGFR（索拉非尼）抑制剂或靶向突变型KRAS信号传导下游标志物的联合治疗（厄洛替尼+ AKT抑制剂MK-2206或MK-2206 + MEK抑制剂AZD-6244）的4个治疗组之一。作为这项临床研究的辅助，我们将进行KRAS信号传导的机制研究，探索特定类型突变KRAS的影响，并在来自BATTLE-2试验的患者组织中开发和测试KRAS激活途径的机制。我们已经从BATTLE-1中注释了临床数据和活检样本，完全支持这种方法的可行性，并可用于验证我们的发现。具体目标包括：1）进行多组、基于活检的前瞻性试验（BATTLE-2）将测试分子靶向药物在选定的难治性NSCLC患者中的疗效，根据正在进行的肿瘤分子标志物分析，通过有限（第1阶段）然后改进（第2阶段）的适应性随机化算法进行治疗分配; 2）使用临床前NSCLC模型研究突变KRAS信号传导的新机制;和3）开发和测试来自BATTLE-2的患者来源样品中KRAS介导的敏感性和抗性的分子标记/特征。我们的总体目标是确定晚期难治性NSCLC患者从选定靶向治疗中获益的预测性生物标志物，发现并阐明突变型KRAS信号在NSCLC中的作用，并确定新的靶点和潜在疗法，以减轻突变型KRAS在NSCLC患者中的影响。这一总体策略是我们手中一种经过验证的方法，鉴于NSCLC患者人群庞大，将有助于重要的知识，并最终改善肺癌患者的结局。

DESCRIPTION (provided by applicant): Lung cancer is a major cause of cancer-related death worldwide, and the prognosis for metastatic NSCLC patients remains poor, with a 5-year survival rate of less than 16%. Our group conducted the first completed, biomarker-driven clinical program titled Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE-1), which incorporated a personalized medicine approach for the treatment of NSCLC; however, resistance to new targeted NSCLC therapies is still an unresolved medical challenge. KRAS is mutated in up to 30% of NSCLC cases and activates multiple signaling pathways that abrogate the effects of many targeted agents being developed for NSCLC; thus, addressing mutant KRAS remains the primary unmet need for NSCLC therapy. We propose to study mechanisms of KRAS signaling and its effects on response to inhibitors of its downstream signaling pathways through our prospective, adaptively randomized trial "BATTLE- 2 Program: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer" (BATTLE-2). We will build on knowledge gained from BATTLE-1, including preliminary findings that specific types of KRAS mutation may be correlated with clinical outcome. In BATTLE- 2, patients with refractory NSCLC will undergo a mandated fresh biopsy and, guided by molecular analyses of their tumors, be adaptively randomized to one of 4 arms with an EGFR (erlotinib) or RAF/VEGFR2/PDGFR (sorafenib) inhibitor, or combinations targeting downstream markers of mutant KRAS signaling (erlotinib + AKT inhibitor MK-2206, or MK-2206 + MEK inhibitor AZD-6244). As an adjunct to this clinical study, we will conduct mechanistic studies of KRAS signaling, explore effects of specific types of mutant KRAS, and develop and test a mechanistic KRAS-activated pathway signature in patients' tissue derived from the BATTLE-2 trial. We have annotated clinical data and biopsy samples from BATTLE-1 that fully support the feasibility of this approach and can be used for validation of our discoveries. Specific aims include: 1) To conduct a multi-arm, biopsy- based prospective trial (BATTLE-2) that will test the efficacy of molecularly targeted agents in selected patients with refractory NSCLC, with treatment assignments by a limited (Stage 1) and then refined (Stage 2) adaptive randomization algorithm based on ongoing analyses of tumor molecular markers; 2) To investigate novel mechanisms of mutant KRAS signaling using preclinical NSCLC models; and 3) To develop and test molecular markers/signatures for KRAS-mediated sensitivity and resistance in patient-derived samples from BATTLE-2. Our overall goals are to identify predictive biomarkers of benefit from selected targeted therapies for patients with advanced, refractory NSCLC, discover and elucidate the role of mutant KRAS signaling in NSCLC, and identify new targets and potential therapies that will mitigate the effects of mutant KRAS in NSCLC patients. This overall strategy is a proven approach in our hands and, given the large population of NSCLC patients, will contribute important knowledge and ultimately result in improved outcomes for patients with lung cancer.