Program Leader: Susan HorwitzCo-Program Leader: Roman Perez-Soler
Research in the Experimental Therapeutics program encompasses preclinical drug development in the areas of transition-state inhibitors, novel microtubule-stabilizing agents, targeted drugs, antifolates and a broad spectrum of biologicals including tumor-targeted monoclonal antibodies linked to radionuclides, aptamers, high-affinity antibodies, drugs designed to modulate apoptotic pathways and agents targeted to surface glycans. AECC’s seminal structural and biochemical studies on the immune synapse are now focused on identification of inhibitor molecules that suppress the immune response to tumors. These studies have become much more clinically relevant with the approval of ipilimumab for cancer treatment and the search for agents that block other immune-inhibitory molecules. Structures were obtained for (i) the PD-1/PD-L2 complex, (ii) human B7-H3 and (iii) human B7-H4, immuno-inhibitory molecules expressed on tumors, providing a structural and mechanistic basis for the identification of agents that selectively manipulate these pathways. Most recently, the structure of the ipilimumab-CTLA4 complex was solved demonstrating that the mechanism by which this mAb blocks CTLA4 function is via direct steric competition with the B7 ligands. This structure also highlighted the determinants that allow the antibody to distinguish between CTLA4 and CD28, thus affording the specificity required for therapeutic efficacy. There have been a number of bench-to-bedside achievements. Two transition-state inhibitors of purine nucleoside phosphorylase are in clinical studies for the treatment of T-cell malignancies. A methylthioadenosine phosphorylase transition-state inhibitor with a broad spectrum of activity in solid tumors is in the pipeline and several additional transition-state inhibitors are in development directed to important targets in neoplasia. A monoclonal antibody linked to 188Rh for the treatment of melanoma has completed Phase I studies. Menadione, identified in preclinical studies as an agent for the prevention/treatment of the dermatitis due to EGFR inhibitors, is in a clinical trial. Structural analyses of Taxol and discodermolide binding to the tubulin pharmacophore by hydrogen-deuterium exchange has led to the development of a novel hybrid inhibitor. Disease-site working groups bring together clinical and laboratory investigators in correlative and therapeutic studies particularly in the areas of breast, gynecological, lung, and head and neck cancers, with emerging groups in neuroendocrine tumors and neuro-oncology. AECC clinical investigators play important roles in national cooperative groups.
Selected Achievements of the Experimental Therapeutics program