NYU Dentistry Collaboration Awarded $8M NIH Grant for Oral Cancer Pain Research

4/05/24

Researchers at NYU Dentistry’s Pain Research Center have been awarded a five-year National Institutes of Health grant to study signaling mechanisms that generate oral cancer pain. The funding is part of the NIH’s Helping to End Addiction Long-term (HEAL) Initiative, which supports the development of safe and effective therapeutics to treat pain in an effort to end the opioid crisis.

Collaborating scientists will investigate signaling receptors located within endosomes, an organelle in cells. These receptors, termed G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs), control many physiological and pathological processes including cancer pain and other forms of chronic pain.

The work supported by the NIH HEAL award (RM1DE033491) will explore the hypothesis that GPCRs and RTKs within endosomes generate long-lasting signals in nerves that carry pain signals (nociceptors) and adjacent cells (Schwann cells) to initiate or mediate pain. Malignant cells within the oral cancer microenvironment along with immune cells and neurons release substances (proteases, neuropeptides, and growth factors) that activate GPCRs and RTKs on nociceptors. GPCRs and RTKs are subsequently internalized within endosomes where they generate signaling complexes that initiate and sustain pain through ion channel expression and long-lasting sensitization of nociceptors. Schwann cells are also implicated in this process.

The team of collaborating principal investigators includes NYU Pain Research Center scientists Drs. Yi Ye, Nigel Bunnett, and Brian Schmidt, as well as Dr. Kam Leong at Columbia University’s Department of Biomedical Engineering and Dr. Rajesh Khanna at University of Florida. Dr. Leong has collaborated with Drs. Bunnett and Schmidt for the past five years; they share an NIH R01 HEAL Award and a fellow from Dr. Leong’s group will be based in the NYU Pain Research Center. In addition, Dr. Nathalie Pinkerton of the Department of Chemical and Biomolecular Engineering at NYU Tandon School of Engineering is a co-investigator on the study. NYU Dentistry’s Dr. Donna Albertson will serve as project director and Dr. Ryan Ruff, director of the NYU Dentistry Biostatistics Core, will serve as the statistician.

The work supported by the NIH award, funded under the HEAL Initiative Integrated Basic and Clinical Team-based Research in Pain, requires diverse expertise in both clinical and basic science. Dr. Schmidt will measure oral cancer pain in patients at the NYU Oral Cancer Center, collecting and studying tumor samples removed at the time of surgery. Dr. Ye will isolate Schwann cells from lingual nerves from these oral cancer patients. Dr. Khanna, an expert on ion channels and sensitization of nociceptors, will study the effects of GPCR and RTK ligands and of cancer supernatant on the activity of nociceptors and Schwann cells. Drs. Ye and Schmidt, who also have expertise in preclinical models of oral cancer pain, will examine the effects of GPCR and RTK ligands and cancer supernatant on pain. Dr. Bunnett holds expertise in GPCR and RTK trafficking and signaling; he pioneered the concept that GPCRs in endosomes (eGPCRs) control pain, which serves as the framework for the study. He will investigate GPCR and RTK trafficking, signalosome assembly and compartmentalized signaling in nerves and Schwann cells.

Dr. Leong and Dr. Pinkerton are bioengineers with expertise in nanoparticle drug delivery, including nanoparticles that deliver GPCR antagonists to endosomes for pain treatment. These investigators will generate nanoparticles containing antagonists of eGPCRs and eRTKs (RTKs in endosomes). The nanoparticles will be studied by Drs. Bunnett, Khanna, Schmidt and Ye in assays of eGPCR and eRTK signaling, sensitization of nociceptors and Schwann cells, and in preclinical models of oral cancer pain. These studies will determine the contribution of eGPCR and eRTK signaling to pain.

Dr. Charles Bertolami, Herman Robert Fox Dean of NYU Dentistry, said the study is “a promising consilience of science and engineering that leverages the expertise and infrastructure of the NYU Pain Research Center and the NYU Oral Cancer Center to foster collaboration between clinical researchers, basic scientists and bioengineers.”