BM-15TARGETING MEK IS A NOVEL AND EFFECTIVE TREATMENT STRATEGY OF LUNG CNS METASTASIS

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2014-11, Vol.16 (Suppl 5), p.v35-v35
• Main Authors: Johnson, Kyle N., Gooden, Gerald, Gonzalez, Paul, Sepulveda, Mario, Gorgol, Loren, Petricoin, Emanuel F., Pierobon, Mariaelena, Byron, Sara, Glen, Jennifer, Ahluwalia, Manmeet, Bernstein, Mark, Toms, Steven A, Salhia, Bodour
• Format: Article
• Language: English
• Subjects: Abstracts
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/nou240.15

There is an urgent need to introduce novel therapies that prevent death due to lung cancer CNS metastasis, which remains a clinically unmet need. Targeted molecular therapies and prophylactic measures might shift the current strategy and improve outcomes. Accordingly our study has focused on identifying novel monotherapies and combination therapies that are based on causal, actionable molecular derangements in lung cancer CNS metastasis, and which can be effectively targeted within the context of the brain microenvironment. We have recently established 6 novel patient-derived cell-lines and matching mouse xenograft models of lung CNS metastasis for preclinical testing of novel therapeutic approaches. Cell-lines were implanted intra-cardiacally for confirmation of CNS homing potential. Therapeutic selections for in vivo testing were based on systems biology-based analyses of the matching clinical material using genomic, epigenomic and phosphoproteomic analyses, which revealed systemic biochemical changes that are druggable. Matching datasets were generated for each cell-line and xenograft to ensure the effectiveness of models in representing the human disease. Primary lung tumors were analyzed when available (2/6 cases). Data analysis revealed defects in KRAS activation due to amplifications, mutations and signaling. Therefore, we proceeded to examine the anti-tumor effects of the MEK inhibitor, PD032591 for in vivo targeting of KRAS. There was >90% inhibition of tumor growth and prolonged survival of animals when treated for 14-30 days with PD032591 in an ectopic or orthotopic setting. Signaling architecture was analyzed pre and post treatment and demonstrated strong attenuation of phospho-ERK without concomitant activation of compensatory mechanisms. We are also currently performing a comprehensive functional screen to identify a synergistic combination strategy for use with PD032591 by testing over 300 clinically available compounds. This first-of-its-kind study has demonstrated a strong preclinical rationale for targeting MEK in lung cancer CNS metastasis with KRAS alterations.