Cancer pain has a major impact on quality of life and clinical treatment of patients. Oral cancer patients rate pain as their worst symptom. Effective treatment of cancer pain remains a critical, unmet goal in cancer research. The proposed study will provide a molecular rationale for the development of mechanism-based therapeutic treatments to reduce oral cancer pain, and cancer pain in general, and allow patients to regain their function. Cancer cells and cancer-associated stromal cells secrete a complex ensemble of bioactive factors into their surroundings to promote cancer growth. A subset of these molecules also sensitizes nociceptors on nearby primary afferent sensory neurons, creating crosstalk among nociception and cancer growth pathways. The proposed research is a targeted sampling and proteomic approach to characterize pain-producing proteases and peptides within the cancer microenvironment. The experimental advantage of our intraoperative microdialysis collection technique is the direct sampling of cancer-associated proteins and peptides in vivo. The nociceptive effect of molecules will be evaluated and confirmed using a well- established cancer pain mouse model. Secreted proteases are promising, yet largely unexploited drug targets for manipulating the levels of pain-producing peptides. We hypothesize that selective inhibition of specific proteases will decrease levels of nociceptive peptides in the cancer environment and relieve cancer-associated pain. The data generated from the proposed studies will provide the molecular basis for an entirely new perspective with which to understand and treat cancer pain.
The Public Health relevance of this project is that successful completion will provide the foundation for a clinical trial based on the pain-producing molecules that we discover. Ultimately, this work could lead to improved treatment for cancer pain.
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