TRPV1 nociceptors in oral carcinogenesis and pain

Project Summary
Oral cancer pain is more severe than all other cancers. Patients with metastatic oral cancer experience the
greatest pain. Oral cancers activate neurons and produce pain; however, the effect of nociceptors on oral
cancer is largely unknown. The mechanisms of reciprocal interaction between oral cancer and neurons, and
how the interactions promote cancer and pain, are not known. The long-term goal is to improve management
of oral cancer patients and obviate opioids by identifying components of the cancer microenvironment that are
viable targets to treat cancer and oral cancer pain. The overall objectives for this application are to (i) elucidate
the phenotype and distribution of transient receptor potential channel, vanilloid subfamily member (TRPV1) +
neurons innervating painful and metastatic oral cancers, (ii) measure sensitization and activation of TRPV1+
neurons by mediators secreted by oral cancer, and (iii) determine the contribution of TRPV1+ neurons to oral
carcinogenesis. The central hypothesis is that oral cancers release mediators, including mediators carried in
extracellular vesicles (EVs) that sensitize and activate nociceptors inducing oral cancer pain. The cancer-
primed nociceptors, in turn, promote cancer. The rationale for the project is that identification of components of
the cancer-nerve interaction provides the opportunity to develop approaches to treat oral cancer and oral
cancer pain, thereby reducing use of opioids. The central hypothesis will be tested by pursuing three specific
aims: 1) Determine the type and density of innervation in oral cancers in relation to pain and metastasis; 2)
Investigate sensitization of trigeminal (TG) neurons by cancer pain mediators; and, 3) Investigate cancer
promotion by cancer activated and sensitized TRPV1+ neurons and evaluate the potential to stop cancer and
alleviate cancer pain by antagonizing signaling via the sensory neuropeptide, calcitonin gene related peptide
(CGRP). Under the first aim, neuronal innervation of the cancer will be evaluated in a retrospective patient
cohort with known pain and nodal status, and testing for capsaicin (TRPV1 agonist) sensitivity and
measurement of pain will be performed in prospectively enrolled oral cancer patients. For the second aim, a
gene associated with pain and metastasis and miRNAs from EVs will be investigated as pain mediators. For
the third aim a mouse oral carcinogenesis model will be used to investigate the impact of TRPV1 abundance
on cancer incidence and phenotype, the impact of CGRP signaling on cancer promotion, and the potential for
CGRP/CGRP receptor therapies for treating and preventing oral cancer and oral cancer pain. The research
proposed is innovative because it is based on two new findings regarding oral cancer pain: (1) newly identified
putative cancer pain mediators overexpressed in metastatic cancers from patients reporting high levels of pain,
and (2) involvement of EVs in cancer induced nociceptive behavior. The proposed research is significant
because these studies will lay the foundation for clinical trials to assess CGRP and CGRP receptor targeted
therapies, which are FDA-approved for migraine, to treat cancer and attenuate cancer pain.

Grant Number: 5R01CA231396-05
NIH Institute/Center: NIH
Principal Investigator: Donna Albertson