Preventive Analgesia for Bone Cancer Pain

描述（由申请人提供）：骨癌疼痛显著降低了每年数百万癌症患者的生活质量和功能状态。 目前，我们对肿瘤在骨中转移和生长时感觉神经纤维如何变化的看法是，神经纤维首先被肿瘤/基质细胞释放的因子致敏和激活，然后随着肿瘤和基质细胞增殖和重塑肿瘤承载骨而受损。 然而，我们已经产生的初步数据表明，肿瘤和肿瘤相关的基质细胞也诱导支配骨的感觉和交感神经纤维的戏剧性发芽和神经瘤形成。 我们的假设是肿瘤和基质细胞诱导TrkA+神经纤维的显著重组，并且这些神经纤维的病理重组在驱动骨癌疼痛中起重要作用。 基于这些观察，我们假设：（1）肿瘤细胞和基质细胞释放的神经生长因子（NGF）诱导TrkA+，而不是TrkA-，感觉和交感神经纤维显着发芽和神经瘤形成;（2）新生的感觉神经纤维具有独特的形态学和病理学上高水平的神经递质、离子通道、受体和丝裂原活化蛋白激酶的表达，这与支配正常骨的神经纤维不同，和（3）早期施用抗NGF或TrkA拮抗剂将比晚期施用更有效地阻断这些病理变化和骨癌疼痛的严重性。 总体假设是，开始给予抗NGF或TrkA阻断剂越早，这些疗法越有可能阻断肿瘤诱导的神经发芽、神经瘤形成、离子通道的不适当上调和疼痛。 如果正确的话，该项目产生的数据有可能从根本上改变我们对骨癌疼痛驱动机制的理解，并促进预防性镇痛用于管理骨癌疼痛。

DESCRIPTION (provided by applicant): Bone cancer pain significantly decreases the quality of life and functional status for millions of cancer patients each year. Currently, our vision of how sensory nerve fibers change when tumors metastasize and grow in bone is that nerve fibers are first sensitized and activated by factors released by tumor/stromal cells, then injured as tumor and stromal cells proliferate and remodel the tumor bearing bone. However, preliminary data we have generated suggests that tumor and tumor-associated stromal cells also induce dramatic sprouting and neuroma formation of sensory and sympathetic nerve fibers that innervate the bone. Our hypothesis is that tumor and stromal cells induce a marked reorganization of TrkA+ nerve fibers and that the pathological reorganization of these nerve fibers plays a significant role in driving bone cancer pain. Based on these observations, we hypothesize that: (1) nerve growth factor (NGF) released from tumor and stromal cells induces marked sprouting and neuroma formation in TrkA+, but not TrkA-, sensory and sympathetic nerve fibers; (2) newly sprouted sensory nerve fibers have a distinct morphology and pathologically high expression levels of neurotransmitters, ion channels, receptors and mitogen-activated protein kinases, which is different from nerve fibers that innervate the normal bone, and (3) early administration of anti-NGF or TrkA antagonist will block these pathological changes and the severity of bone cancer pain more effectively than late administration. The overarching hypothesis is that the earlier administration of anti-NGF or TrkA blockade is begun, the more likely these therapies will block tumor-induced nerve sprouting, neuroma formation, inappropriate up-regulation of ion channels, and pain. If correct, data generated from this project has the potential to fundamentally change our understanding of the mechanisms that drive bone cancer pain and promote the use of preventive analgesia for managing bone cancer pain.