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 i nclude: 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.
Lung cancer is a major cause of cancer-related death worldwide. The BATTLE-2 project incorporates a personalized medicine clinical trial approach for the treatment of non-small cell lung cancer (NSCLC) with laboratory-based studies of biological mutations. This dual approach will provide important knowledge regarding how mutations impact overall cancer prognosis and which treatment agents effectively mitigate certain mutations, potentially allowing physicians to predict which patients will derive the most treatment benefit.
|Liu, Huafeng; Li, Xin; Hu, Li et al. (2017) A crucial role of the PD-1H coinhibitory receptor in suppressing experimental asthma. Cell Mol Immunol :|
|Shien, Kazuhiko; Papadimitrakopoulou, Vassiliki A; Ruder, Dennis et al. (2017) JAK1/STAT3 Activation through a Proinflammatory Cytokine Pathway Leads to Resistance to Molecularly Targeted Therapy in Non-Small Cell Lung Cancer. Mol Cancer Ther 16:2234-2245|
|Choi, M; Kadara, H; Zhang, J et al. (2017) Mutation profiles in early-stage lung squamous cell carcinoma with clinical follow-up and correlation with markers of immune function. Ann Oncol 28:83-89|
|Kadara, H; Choi, M; Zhang, J et al. (2017) Whole-exome sequencing and immune profiling of early-stage lung adenocarcinoma with fully annotated clinical follow-up. Ann Oncol 28:75-82|
|Papadimitrakopoulou, Vassiliki; Lee, J Jack; Wistuba, Ignacio I et al. (2016) The BATTLE-2 Study: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small-Cell Lung Cancer. J Clin Oncol :|
|Riquelme, Erick; Behrens, Carmen; Lin, Heather Y et al. (2016) Modulation of EZH2 Expression by MEK-ERK or PI3K-AKT Signaling in Lung Cancer Is Dictated by Different KRAS Oncogene Mutations. Cancer Res 76:675-85|
|Gu, Xuemin; Chen, Nan; Wei, Caimiao et al. (2016) Bayesian Two-stage Biomarker-based Adaptive Design for Targeted Therapy Development. Stat Biosci 8:99-128|
|Skoulidis, Ferdinandos; Byers, Lauren A; Diao, Lixia et al. (2015) Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov 5:860-77|
|Schalper, Kurt A; Brown, Jason; Carvajal-Hausdorf, Daniel et al. (2015) Objective measurement and clinical significance of TILs in non-small cell lung cancer. J Natl Cancer Inst 107:|
|Herbst, Roy S; Gandara, David R; Hirsch, Fred R et al. (2015) Lung Master Protocol (Lung-MAP)-A Biomarker-Driven Protocol for Accelerating Development of Therapies for Squamous Cell Lung Cancer: SWOG S1400. Clin Cancer Res 21:1514-24|
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