Targeting Succinate Signaling for Innovative Pain Relief in Oral Cancer.

Current pain management strategies for patients with oral or head and neck cancer conditions often rely on high-dose opioid analgesics, which can be ineffective. Succinate is a dicarboxylic acid metabolite in the Krebs cycle, and emerging evidence highlights its pro-inflammatory role through the activation of its G-protein coupled receptor, SUCNR1. Notably, oral cancer patients show elevated circulating succinate levels and increased SUCNR1 expression in tumor tissues. We have been at the forefront of investigating succinate/SUCNR1 signaling and have demonstrated that SUCNR1 activation prompts pro-inflammatory signaling in myeloid cells. Our preliminary findings indicate that patients with oral cancer experiencing higher pain scores have elevated plasma succinate levels. Additionally, SUCNR1 expression has been observed in both human and mouse ganglia, with succinate increasing inflammation and nociception in wildtype (WT) mice but not in SUCNR1 knockout (KO) mice. In an MOC2 orthotopic xenograft model of oral cancer, KO mice exhibited reduced facial nociception and fewer tumor- infiltrating myeloid cells. We hypothesize that inhibiting SUCNR1 activation could alleviate oral cancer pain by reducing inflammation and nociception. To test this hypothesis, we propose two specific aims. In Aim 1, we will investigate succinate signaling and assess SUCNR1 as a potential target for alleviating oral cancer pain using clinical samples and preclinical models. The analgesic effects of a novel SUCNR1 antagonist we have developed will be evaluated in 4NQO-induced oral cancer mice. We will measure tumor growth, oral function, and referred mechanical and thermal hypersensitivities, along with associated comorbidities. Additionally, we will explore the distribution and neuromodulatory function of SUCNR1 in human oral cancer tissues, and the ganglia of both human and mouse. In Aim 2, we will evaluate the role of myeloid SUCNR1 in oral cancer pain with global and myeloid-specific knockout mice, alongside their littermate controls. Three oral cancer models—MOC1 and MOC2 orthotopic xenografts and 4NQO-induced oral cancer—will be developed in these mice. We will measure tumor growth and nociception while characterizing various myeloid populations in tumor, peripheral blood, and tumor- draining lymph nodes through flow cytometry. Lastly, we will assess succinate and cytokine levels in serum, and tumor tissues using succinate assays, Meso Scale Discovery multiplex immunoassays, and semi- quantitative PCR.