Personalizing NSCLC Therapy: Exploiting KRAS activated pathways

描述(申请人提供)：肺癌是全球癌症相关死亡的主要原因，转移性非小细胞肺癌患者的预后仍然很差，5年生存率不到16%。我们团队开展了首个完整的、由生物标记物驱动的临床项目，名为《消除肺癌的生物标记物综合靶向治疗方法》(BATE-1)，其中包含了治疗非小细胞肺癌的个性化药物方法；然而，对新的靶向非小细胞肺癌疗法的耐药性仍然是一个悬而未决的医学挑战。KRAS在高达30%的NSCLC病例中发生突变，并激活多个信号通路，从而消除许多正在为NSCLC开发的靶向药物的效果；因此，解决突变的KRAS仍然是NSCLC治疗的主要未满足需求。我们建议通过我们的前瞻性适应性随机试验“BATE-2计划：一项针对既往治疗过的晚期非小细胞肺癌患者的生物标记物整合靶向治疗研究”(BATE-2)，研究KRAS信号转导机制及其对其下游信号通路抑制剂的反应。我们将建立在从Batch-1中获得的知识的基础上，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试验中，难治性NSCLC患者将接受强制的新鲜活检，并在对他们肿瘤的分子分析的指导下，被适应性地随机分配到4组中的一组，使用EGFR(Erlotinib)或RAF/VEGFR2/PDGFR(Sorafenib)抑制剂，或针对突变KRAS信号的下游标记的组合(erlotinib+AKT抑制剂MK-2206或MK-2206+MEK抑制剂AZD-6244)。作为这项临床研究的补充，我们将进行KRAS信号的机制研究，探索特定类型突变KRAS的影响，并开发和测试来自BATE-2试验的患者组织中的机制KRAS激活的通路信号。我们有来自BARAT-1的临床数据和活检样本的注释，这充分支持了这种方法的可行性，并可用于验证我们的发现。具体目标包括：1)进行一项多臂、以活检为基础的前瞻性试验(BARAT-2)，该试验将测试分子靶向药物在选定的难治性非小细胞肺癌患者中的疗效，采用基于持续分析肿瘤分子标志物的有限(第一阶段)然后改进(第二阶段)自适应随机化算法进行治疗；2)利用临床前NSCLC模型研究突变的KRAS信号的新机制；以及3)开发和测试KRAS介导的敏感性和耐药性的分子标志物/签名。我们的总体目标是为晚期难治性非小细胞肺癌患者确定受益于选定靶向治疗的预测性生物标记物，发现并阐明突变的KRAS信号在非小细胞肺癌中的作用，并确定新的靶点和潜在的治疗方法，以减轻突变的KRAS对非小细胞肺癌患者的影响。这一总体战略在我们手中是一种经过验证的方法，考虑到大量的非小细胞肺癌患者，它将贡献重要的知识，并最终改善肺癌患者的预后。

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.