The Role of Proteases and Peptides in Cancer Pain

描述(申请人提供)：癌症疼痛对患者的生活质量和临床治疗有重大影响。口腔癌患者认为疼痛是他们最严重的症状。癌症疼痛的有效治疗仍然是癌症研究中一个关键的、尚未实现的目标。这项拟议的研究将为开发基于机制的治疗方法提供分子基础，以减少口腔癌疼痛，并总体上减轻癌症疼痛，并使患者恢复功能。癌细胞和与癌症相关的基质细胞分泌一组复杂的生物活性因子进入其周围，以促进癌症的生长。这些分子的一个子集还使附近初级传入神经元上的伤害性感受器变得敏感，在伤害性感受和癌症生长途径之间产生串扰。这项拟议的研究是一种有针对性的采样和蛋白质组学方法，以表征癌症微环境中产生疼痛的蛋白酶和多肽。我们术中微透析收集技术的实验优势是可以在体内直接采样癌症相关蛋白和多肽。分子的伤害性效应将使用已建立的癌症疼痛小鼠模型进行评估和确认。分泌的蛋白酶是很有希望的，但在很大程度上还没有被开发的药物靶标，用于操纵产生疼痛的多肽的水平。我们假设，选择性抑制特定的蛋白酶将降低癌症环境中伤害性多肽的水平，并缓解与癌症相关的疼痛。拟议研究产生的数据将为理解和治疗癌症疼痛的全新视角提供分子基础。

DESCRIPTION (provided by applicant): 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.