Contribution of Truncated TrkB Isoform in Oral Cancer Pain

Project Summary This research will address the critical issue of pain in patients with head and neck carcinoma (HNC), which significantly impairs their quality of life. Many HNC patients require opiate pain management, but tolerance develops quickly, necessitating new pain relief approaches. Tyrosine kinase receptors (Trk) have gained

attention due to emergence of small-molecule inhibitors for cancer treatment. Brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, are known to be overexpressed in oral tumors and implicated in cancer progression. Additionally, we have demonstrated the role of the BDNF-TrkB axis in oral cancer

pain at the site of tumor growth. Specifically, we have shown that BDNF released from oral squamous cell carcinoma (OSCC) cells influences pain transmission, which can be reversed by inhibiting TrkB locally. Importantly, the truncated TrkBT1 isoform that is recently shown to be dominant in oral tumors, is less explored than its full-

length counterpart. Our preliminary data suggest that TrkBT1 is a predominant isoform in trigeminal sensory neurons as well as in OSCC cells and is involved in oral cancer pain regulation. Accordingly, we propose to test the central hypothesis that peripherally expressed TrkBT1 in trigeminal sensory neurons and OSCC cells

contributes to sensory neuronal plasticity and tumor microenvironment respectively. Specific aim 1 will include investigating TrkBT1's role in sensory neurons and its impact on pain behaviors, neuronal plasticity, and gene expression. Aim 2 will involve examining whether OSCC-derived TrkBT1 regulates pain-associated changes in the

tumor microenvironment by assessing immune cell profiles, transcriptomic changes, and single-cell analysis in tongue tumors. Additionally, the potential of targeting TrkBT1 for the treatment of oral tumorigenesis and cancer- induced pain will be evaluated. This study will offer novel insights into truncated TrkBT1 biology, oral cancer pathophysiology, and

cancer-induced pain. Findings may have broader implications for other cancer types and orofacial pain conditions. Translational and medical significance is strengthened by potentially identifying new therapeutic options for oral cancer and cancer-induced pain. RELEVANCE: It is often very difficult to treat pain from oral cancer with available medications due to limited

effectiveness or rapid development of tolerance. We propose a highly novel mechanism that will evaluate the peripheral role of Truncated TrkB (TrkBT1) isoform in oral cancer pain. This study's relevance lies in its potential to uncover novel therapeutic targets for managing oral cancer-induced pain and improving patients' quality of

life. By investigating the role of TrkBT1 in both sensory neurons and the tumor microenvironment, the research may pave the way for innovative treatments that address pain and oral tumorigenesis simultaneously.