Description:

The Department of Pharmacology encourages you to attend a seminar, presented by Feinberg's own, Andrew P. Mazar, Ph.D., Professor, Department of Pharmacology, Director, Center for Developmental Therapeutics, and Entrepreneur-in-Residence, Chemisty of Life Processes Unit.

The following, is an overview of this seminar, as described by Dr. Mazar:

"Numerous targeted drugs have been developed for the treatment of cancer. However, many of these drugs are either ineffective or poorly effective and often lead to only modest improvements in clinical outcomes especially in patients with advanced disease that have failed multiple treatments because tumors develop compensatory mechanisms that circumvent the targeted treatment. We have hypothesized that despite having the ability to circumvent many targeted therapies, tumors may express nodes through which multiple oncogenic pathways cross and that these nodes might represent chokepoints. Targeting these chokepoints might therefore simultaneously inhibit multiple signaling pathways that drive tumor progression and result in novel therapeutics that would lead to more robust and durable clinical responses. We have identified two such chokepoints: the urokinase plasminogen activator receptor (uPAR) and nuclear glycogen synthase kinase-3 (GSK-3). uPAR may physically assemble a signalosome at the tumor cell surface that drives tumor progression and contains various drivers of proliferation such as integrins, EGFR, PDGFR, SRC, FAK and others. Nuclear GSK-3 is a positive regulator of NF-B mediated gene transcription and can regulate the expression of a number of oncogenic effector molecules that mediate chemoresistance. Further, we have hypothesized that there is cross-talk between uPAR and GSK-3, driving tumor chemoresistance and metastasis. We have developed novel inhibitors for both of these targets that are now in pre-clinical development and have used these to demonstrate robust antitumor activity and the ability to reverse chemoresistance in vitro and in vivo. Further studies are underway to elucidate the molecular choreography mediated by uPAR and GSK-3 that drives tumor progression."