The National Institute of Dental and Craniofacial Research has awarded a $3.7 million, five-year grant to Brian Schmidt, DDS, PD, PhD, of the Bluestone Center for Clinical Research at the New York University College of Dentistry and Nigel Bunnett, PhD, of Columbia University’s departments of surgery and pharmacology to study the proteases and neuronal signaling that are responsible for oral cancer pain.
Oral cancer is notoriously painful. The pain signaling mechanisms responsible for cancer pain are not well understood. 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. Previously, the researchers investigated the role of proteases in oral cancer pain when they were members of the faculty at the University of California San Francisco in 2009.
Now, Schmidt and Bunnett will attempt to unequivocally identify tumor-generated proteases and define the signaling pathway from the proteases to the receptors on the surface of a nerve to the endosomes within the nerve. Schmidt will use 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,” said Schmidt. “This work has obvious implications for treating patients and may lay the foundation for development of a new class of drugs to treat cancer pain and chronic pain without opioids.”
Bunnett will use high-resolution imaging and molecular probes on patient tumors to track G protein-coupled receptors (GPCR) intracellularly after cell surface activation. Previously, he has studied how proteases and a specific GPCR known as protease-activated receptor 2 (PAR2) mediate neurogenic inflammation and pain. PAR2 is a signaling receptor that can be activated on the surface of a cell.
“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,” said Bunnett.
More recently, Bunnett has investigated PAR2 and endosomal signaling. During the signaling process, an activated cell surface receptor such as PAR2 is internalized within endosomes, which are small, membrane-bound compartments within a cell.
“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,” Bunnett said.
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.
“Using drugs designed by Dr. Bunnett’s lab, we can trace pain signaling at a molecular level within the nerve,” said Schmidt. “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.”
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