Mechanisms of resistance to MEK Inhibition in RAS-pathway activated chronic myelomonocytic leukemia

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PROJECT SUMMARY/ABSTRACT Overview: The goal of this award is to provide Dr. Ami Patel with the training and mentored research experience to ensure success in her transition to an independent investigator with expertise in the biology and treatment of myeloid malignancies. Dr. Patel’s long term goal is to create and support an independent laboratory-based translational research program dedicated to the investigation of targeted drug resistance in myeloid neoplasms. Research: Chronic myelomonocytic leukemia (CMML) is an aggressive hematologic malignancy associated with dismal survival outcomes and low curative potential. Treatment options are extremely limited, poorly tolerated and fail to address many disease-related symptoms. Targeted agents represent a promising therapeutic opportunity for CMML patients with mutations that lead to aberrant signal transduction through the RAS/mitogen activated kinase (MAPK) pathway. The proposed research aims to understand whether this subset of CMML patients could benefit from treatment with cobimetinib, a specific inhibitor of RAS/MAPK signaling. The proposal includes a clinical trial to test the efficacy of cobimetinib in CMML patients with RAS/MAPK activation. Unfortunately, clinical experience with targeted inhibitors support the eventual emergence of drug resistance. The proposed research aims to understand, prevent and overcome anticipated MEK inhibitor resistance. Longitudinal samples from patients treated on the cobimetinib trial will be analyzed using whole exome and RNA sequencing to identify biomarkers of drug resistance. Laboratory-based preclinical studies will utilize advanced high throughput sequencing and target validation methodologies in cell lines, primary CMML cells and patient derived xenograft models of CMML to help identify mechanisms of resistance that can be cross-referenced with clinical trial findings. Pathways implicated in MEK inhibitor resistance may be candidates for targeted inhibition, leading to the development of novel combinatorial treatment strategies in RAS-activated CMML. Career Development: Dr. Patel is an accomplished hematologist-oncologist with a strong background in translational research in myeloid malignancies. However, prior to starting an independent research program, Dr. Patel requires further training in advanced sequencing and bioinformatics analysis, genome editing and techniques and clinical trial implementation and oversight. The structured protected time,didactics and mentoring provided by the K08 will allow Dr. Patel to complete this essential training. Dr. Patel has assembled a highly experienced, diverse and internationally-recognized mentoring team committed to her future success. The Huntsman Cancer Institute, an NCI-designated Comprehensive Cancer Center, and the University of Utah provide a rich and supportive institutional environment for Dr. Patel to advance her career.