Thursday, September 19, 2013
Center for the Chemistry of Cellular Signaling
Overcoming in Vivo Barriers Limiting the Efficacy of Designed Small Molecules Targeting Signal Transduction
Bogdan Olenyuk, Professor, University of Southern California, School of Pharmacy
Conventional, systemic therapies typically rely on a large concentration gradient across the semi‐permeable vascular endothelial cell barrier in order to drive circulating molecules from the bloodstream into the tumor. However, only a small fraction of the intravenously administered dose actually reaches tumor sites. This requires continuously increasing doses in order to achieve some level of therapeutic efficacy and is often leading to systemic toxicity. Thus, the efficacy of many small molecules is seriously compromised by the significant in vivo barriers that inhibit delivery. This seminar will highlight strategies that exploit active transendothelial pathways in order to transport small molecules targeting oncogenic signaling into tumors. Traversing across the vascular endothelium takes advantage of the "caveolae pumping system", giving excellent response in a rigorous in vivo model that appears to closely resemble human tumors. Using intravital microscopy, we conducted comparative assessment of targeting, tumor penetration, and therapeutic response of small molecules in classical subcutaneous and in advanced tumor models. Our results suggest that therapeutic effect of small molecules in overcoming hypoxia‐induced tumor growth and resistance directly depends on the efficiency of their transvascular transport.