THE ROLE OF PERIPHERAL BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) SIGNALING IN ORAL CANCER PAIN

Numerous studies have indicated that pain is the top ranked symptom in head and neck cancer (HNC)patients. However, available treatments are limited and associated with severe side effects addingsubstantially to the burden of having cancer. Thus, there is a critical need for novel analgesics. However, thereis a large gap in knowledge for oral cancer pain mechanisms and thus pain control is often incomplete.Because pain in oral cancer occurs even before a tumor becomes clinically apparent, this cardinal symptomindicates that cancer cells control the activities of surrounding nociceptors at the site of the tumor. Theobjective here is to study a novel mechanism for oral cancer pain by which tumor cells interact with sensoryneurons at the orthotopic site. Our central hypothesis is that Brain-derived neurotrophic factor (BDNF) isreleased from oral squamous cell carcinoma (OSCC) cells and activates adjacent sensory fibers, contributingto OSCC-induced pain. This hypothesis is based on compelling preliminary data demonstrating that BDNFlevels are elevated in oral tumor in mice and that antagonizing the BDNF receptor reverses pain-like behaviorsin vivo. We will employ behavioral, biochemical, anatomical methods as well as electrophysiological analysis oflingual nerve fibers that allows studying tumor-nerve interactions in situ, to study the aims:Aim 1: Determine whether OSCC-released BDNF contributes to oral cancer pain. Using superfusiontechniques, electrophysiology and behavioral assays, this aim will determine the release of BDNF from tonguetumor as well as test whether released BDNF regulate surrounding nerve fibers activities in the tongue andproduce pain-like behaviors in vivo. Results from male and female mice will be compared to determine BDNF-induced sexually dimorphic effects.Aim 2: Determine whether TrkB and p75 receptors (p75R) play a role in BDNF mediated peripheral oral cancerpain. The effects of pharmacological and molecular inhibition on the TrkB and p75 receptors in sensoryneurons will be determined with electrophysiologic recordings. Follow-up experiments will test the effect ofapplication of recombinant human BDNF on sensory fiber activities in nave animals. Sex-dependentdifferences will also be determined.Aim 3: Determine downstream BDNF signaling pathways in mediating oral cancer pain. Using male andfemale mice, this aim will employ anatomical and electrophysiological methods to identify the downstreampathways of TrkB and the p75 receptor that may play a role in BDNF-induced oral cancer pain. Collectively, experiments proposed herein provide critical and comprehensive tests of the centralhypothesis. The translational significance of this project is strengthened by the use of human cancer cells anda clinically relevant orthotopic model that mimics patient symptoms as well as the novel electrophysiologymethod to study tumor-nerve interaction at the very site of tumor development.RELEVANCE: It is often very difficult to treat pain from oral cancer with available medications due to limitedeffectiveness or rapid development of tolerance. We propose a highly novel mechanism that will evaluate theperipheral role of BDNF signaling in oral cancer pain. The research project addresses a significant medicalproblem with an innovative hypothesis and newly developed experimental methods. Moreover, there is astrong rationale for the focus of this application, as BDNF signaling is known to trigger pain and contribute totumor progression and chemoresistance in head and neck cancer.