The National Institute of Dental and Craniofacial Research (NIDCR), part of the National Institutes of Health (NIH), has awarded Brian Schmidt, DDS, MD, PhD, of the Bluestone Center for Clinical Research at New York University College of Dentistry (NYU Dentistry) and Nigel Bunnett, PhD, of Columbia University’s Departments of Surgery and Pharmacology, a $3.7 million, five-year grant to study proteases and neuronal signaling responsible for oral cancer pain.
Oral cancer is notoriously painful. The pain signaling mechanisms responsible for cancer pain are not well understood. Drs. Schmidt and Bunnett seek to identify the proteases – or enzymes that catalyze the breakdown of proteins – and signaling pathways that initiate and sustain oral cancer pain.
Drs. Bunnett and Schmidt collaboratively investigated the role of proteases in oral cancer pain in 2009 when they were both faculty at the University of California San Francisco. Dr. Schmidt moved to NYU Dentistry in 2010 and Dr. Bunnett moved to Monash University in Australia in 2011. In August, 2016, Dr. Bunnett accepted the position of Vice Chair of Research in Surgery and Professor of Surgery and Pharmacology at Columbia University; once again in the same city, Drs. Bunnett and Schmidt renewed their collaboration.
Dr. Bunnett is an internationally recognized expert on G protein-coupled receptors (GPCR); over many years he investigated how proteases and a specific GPCR termed PAR2 (protease-activated receptor 2), mediate neurogenic inflammation and pain. PAR2 is a signaling receptor that can be activated on the surface of a cell. Dr. Bunnett’s landmark Nature Medicine publication in 2000 on the role of PAR2 and neurogenic inflammation set the stage for pioneering work that determined the role of PAR2 and TRPV (a pain-related receptor) in colitis, neurogenic inflammation, and pain. The role of PAR2 in cancer pain, however, remained unexplored. According to Dr. Bunnett, “Brian and I hypothesized that proteases (which we found at high levels in oral cancers), probably induce pain by activating PAR2 on oral nociceptors (nerves that initiate pain signals). Manipulation of the protease/PAR2 axis stands out as a potential therapeutic approach to pain.”
More recently Dr. Bunnett investigated PAR2 and endosomal signaling. During the signaling process an activated cell surface receptor, such as PAR2, is internalized within endosomes – small membrane-bound compartments within a cell. Dr. Bunnett adds, “An activated receptor apparently continues its signaling role while contained in an endosome; to confirm this finding I investigated delivery of pain attenuating drugs into endosomes.” Drs. Bunnett and Schmidt now propose to delineate the mechanism by which proteases associated with oral cancer initiate pain signaling through cell surface receptors and subsequently through endosomal signaling.
Dr. Schmidt’s research program is dedicated to laboratory and clinical investigation of oral cancer pain. Dr. Schmidt describes his current collaboration with Dr. Bunnett as “the culmination of many years of work related to proteases, PAR2, and pain. Using drugs designed by Dr. Bunnett’s lab, we can trace pain signaling at a molecular level within the nerve.” Dr. Schmidt describes Dr. Bunnett’s research on PAR2 as profoundly informative for his work on the molecular mechanisms responsible for oral cancer pain. Dr. Schmidt states, “Dr. Bunnett’s work on GPCR signaling has challenged dogma within the field and refined our understanding of how proteases signal on the cell surface and within intracellular compartments.”
Drs. Bunnett and Schmidt now seek to unequivocally identify tumor-generated proteases and define the signaling pathway from proteases to receptors on the surface of a nerve to the endosomes within the nerve. Dr. Schmidt will utilize pain severity data gathered from his patients along with oral cancer tissue obtained during surgical resection. “My laboratory will study patient tissues to reveal the cellular origin of the proteases,” says Dr. Schmidt. Dr. Bunnett will use high-resolution imaging and molecular probes on patient tumors to track the GPCR intracellularly after cell surface activation. “This work has obvious implications for treating patients,” says Dr. Schmidt, “and may lay the foundation for development of a new class of drugs to treat cancer pain and chronic pain without opioids.”
The research is funded under NIH/NIDCR R01 grant number: R01DE026806-01A1 (Schmidt/Bunnett).