Preventive Analgesia for Bone Cancer Pain

描述（由申请人提供）：骨癌疼痛每年显著降低数百万癌症患者的生活质量和功能状态。目前，我们对肿瘤在骨内转移和生长时感觉神经纤维变化的看法是，神经纤维首先被肿瘤/基质细胞释放的因子致敏和激活，然后在肿瘤和基质细胞增殖和重塑肿瘤承载骨时受到损伤。然而，我们获得的初步数据表明，肿瘤和肿瘤相关的基质细胞也会诱导支配骨骼的感觉和交感神经纤维的急剧发芽和神经瘤的形成。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，这些神经纤维的病理重组在驱动骨癌疼痛中起重要作用。基于这些观察结果，我们假设：(1)肿瘤和基质细胞释放的神经生长因子（NGF）诱导TrkA+、TrkA-、感觉和交感神经纤维显著发芽和神经瘤形成；(2)新生感觉神经纤维形态明显，病理上神经递质、离子通道、受体和丝裂原活化蛋白激酶的表达水平较高，不同于支配正常骨的神经纤维；(3)早期给药抗ngf或TrkA拮抗剂比晚期给药更有效地阻断这些病理改变和骨癌疼痛的严重程度。总的假设是，越早开始使用抗ngf或TrkA阻断剂，这些治疗就越有可能阻断肿瘤诱导的神经发芽、神经瘤形成、不适当的离子通道上调和疼痛。如果正确，该项目产生的数据有可能从根本上改变我们对驱动骨癌疼痛的机制的理解，并促进使用预防性镇痛来管理骨癌疼痛。

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. PUBLIC HEALTH RELEVANCE: Bone cancer pain significantly decreases the quality of life and functional status for millions of patients with metastatic breast, prostate and lung cancer each year. The hypothesis we are testing is that tumors and their associated stromal cells release nerve growth factor which induces a marked and pathological reorganization of nerve fibers which drives bone cancer pain. 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 which may block the development of severe bone cancer pain.