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.
Oral cancer patients suffer from severe, chronic pain, which is induced by release of mediators from the cancer that act on nearby sensory nerves. Sensitized nerves, in turn, secrete factors that potentially modulate growth and metastasis of the cancer. Whilst nerves and epithelial cells normally interact in healthy tissues, a better understanding of the disturbed interactions that occur in cancer can lead to new ways to both treat cancer and alleviate cancer pain.
