Translational Medicine and Cancer Therapy with Vasculature-Targeted Agents

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DESCRIPTION (provided by applicant): Project Summary: The purpose of this K23 proposal is to consolidate the investigator's diverse training experiences into an independent research program that identifies and develops genetic and clinical biomarkers for the individualized management of cancer therapeutics. To accomplish this, Dr. Maitland will: 1) complete additional didactic and tutorial education in pharmacometrics, statistical genetics, and multivariate analysis, 2) be primarily mentored by Dr. Mark Ratain (an internationally recognized expert in both early stage cancer drug development and inter-individual variability in cancer therapeutics) in the design, execution, and interpretation of studies to identify biomarkers for inhibition of the Vascular Endothelial Growth Factor (VEGF) Signaling Pathway (VSP), and 3) be mentored by senior colleagues in the Oncology and Human Genetics Sections of the University of Chicago Biological Sciences Division on relevant genetic analyses, and design and execution of a multi-center study to test the utility of the most promising of the developed biomarkers for inhibition of the VSP. VSP inhibitors constitute a new class of anticancer agents that modify the vasculature and may thereby enhance the efficacy of concurrent chemotherapy. Reliable biomarkers for VSP inhibition do not yet exist but would guide the optimal dosing and selection of VSP inhibitors for a specific patient. To identify and develop such biomarkers the investigator will: 1 Characterize the relationship between the VSP inhibitor sorafenib and blood pressure, and determine the pharmacological basis for interindividual variability in blood pressure response, 2) test candidate gene polymorphisms and clinical variables for contribution to this variability and the relevance of blood pressure variability to treatment response, and 3) test the effects of typical anticancer interventions on serum concentrations of the endothelial cell-synthesized molecule angiopoietin-2(Ang2), determine the intrinsic variables affecting serum concentrations of Ang2, and identify Quantitative Trait Loci (sites for candidate gene variants associated with serum concentrations of Ang2). Relevance: New drugs, and new technologies to guide their use, offer the possibility for physicians to tailor treatment for the specific patient. This "personalized medicine" promises safer, more effective treatment for patients with cancer. This grant will help train Dr. Maitland to be an expert in the conduct of clinical and laboratory studies for personalized cancer medicine.