Defining kinase interaction pathways to enhance anti-cancer efficacy and minimize associated morbidities of kinase inhibitor drugs.

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PROJECT SUMMARY The decreased quality of life and increased morbidity due to oncological drugs such as Tyrosine Kinase Inhibitors (TKIs) is a serious and growing general health problem. In particular, cardiovascular (CV) morbidities are a major detrimental factor affecting the survivorship of cancer patients. The primary roadblock to addressing the toxicity of TKIs is that they inhibit multiple kinases besides those necessary to achieve the anti-cancer effect, but the kinases responsible for CV toxicity are poorly defined. This K99/R00 project supports a productive physician-scientist to identify kinase interaction networks relevant to the anti-cancer and CV toxic effects of TKIs. Preliminary data builds on the candidate’s research leading to the development of analogues of the TKI ponatinib that have greatly reduced toxicity, which can additionally be used as probes of signaling in CV and tumor cells. These studies identified candidate kinases that, when inhibited, are detrimental to cardiomyocyte and endothelial cells, as well as candidate kinases that, when inhibited, elicit potentially protective effects against CV morbidities. By using pharmacological and genetic probes, the broad objectives of the project are 1) determine the comprehensive kinase signaling networks responsible for anti-cancer activity in Chronic Myeloid Leukemia (CML) and the kinases that evoke the CV toxicity in each of the two major CV lineages (cardiomyocytes and vascular endothelial cell) and 2) verify and characterize kinases that, when inhibited, prevent this toxicity. The mentored (K99) phase of the project will focus on elucidating the kinase networks responsible for the anti-cancer effect in CML carrying the drug resistant mutation T315I (K99-Aim1) and for CV toxicity (K99-Aim 1). The independent (R00) phase of the project will examine candidate protective kinases networks (involving inhibition of ROCK1, RAF1 and MAPK11) using xenograft models of CML-T315I treated with ponatinib (R00-Aim1A) and non-small cells lung cancer treated with osimertinib (R00-Aim1B). The proposed research and training plan will prepare the applicant to successfully transition to a productive independent academic career defining mechanisms relevant to the safety and efficacy of oncology drugs. The mentoring plan describes roles of the primary mentor, an Advisory Committee consisting of highly regarded senior PIs at multiple institutions who are experts in clinical and basic science aspects of oncology, drug development and cardio-oncology, and collaborators who are leaders in kinase network mapping, and bioinformatics. The training plan will expand the applicant’s skills in cutting edge technologies such as kinase mapping approaches, mass spectrometry and computational analysis of the high-throughput data, and leadership skills. The training will be a critical factor for R00 independent phase and beyond. Training will take place at Stanford University enabling her to become an independent academic PI and leader in the development of safer and more effective oncology drugs to improve survivorship and life-quality of cancer patients.