Intra-tumoral neurons contribute to head and neck cancer pain

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Project Summary/Abstract Pain is an independent prognostic factor for survival in head and neck cancer (HNC). These cancers can be broadly divided into those that are induced by infection with high-risk human papillomavirus (HPV positive) and those that are mutationally driven (HPV negative). The onset of orofacial pain may signal the pre-cancerous to cancerous transition as well as the recurrence of disease, suggesting a predictive value. Thus, pain is a significant co-morbidity in HNC. Despite this, well-established guidelines for HNC pain management are lacking and opioids remain at the forefront of treatment. Given its influence on patient survival and the widespread risk of opioid dependence, additional therapies are needed to address HNC pain. The presence of neurons within solid tumors is now widely accepted. Our preliminary data show that HPV negative tumors are significantly more innervated than their HPV positive counterparts. Moreover, we show that intra-tumoral neurons are transcriptionally and functionally different from normal (naïve) neurons. In Aim 1, we will test how HPV status and sex influence these characteristics of intra-tumoral neurons and their effects on cancer pain. We have previously published that tumor-released small extracellular vesicles (sEVs) lure neurons to the tumor bed. Our preliminary analysis of sEV miRNAs suggest that these cargo molecules directly impact tumor innervation. In addition, we also show that expression of HNC oncogenes influences the packaging of miRNAs in sEVs. In Aim 2, we will test the effect of sEV miRNAs on cancer pain in vivo. In addition, given the presence of neurons within tumor tissues, we electrophysiologically assessed activity in HNC patient tumor slices. We found that HPV negative tumors harbor a significantly higher electrical activity than those that are HPV positive. We also show that this activity can be pharmacologically attenuated with pain-targeting drugs (e.g. lidocaine). In Aim 3, we will use a pain assessment patient questionnaire and matched patient tumors to determine whether tumoral electrical activity correlates with patient reported pain. We will also test whether drugs that attenuate pain also function to slow/block tumor growth in vivo. Together, the outcomes of these studies will define that intra-tumoral neurons and tumor-released sEVs as critical drivers of HNC pain. Moreover, we will have identified nerve targeting drugs that can attenuate tumor growth and improve survival. These findings will support future clinical trials testing these targets and drugs for the control of cancer pain.