METASTATIC PROSTATE CANCER-INDUCED BONE PAIN

描述(申请人提供)：前列腺癌在癌症中是独一无二的，尽管它是高度转移的，但骨通常是临床上唯一可检测到的转移部位。幸运的是，转移性前列腺癌患者通常存活时间较长。不幸的是，前列腺癌的骨转移经常导致严重的慢性疼痛，降低生活质量和功能状态，并极大地提高卫生保健利用率。该应用程序的目标是了解驱动前列腺癌引起的骨痛的机制，并利用这些信息开发可以更好地预防和/或治疗这种慢性疼痛的疗法。在初步研究中，我们改进了前列腺癌骨痛的小鼠模型，使其在以下方面密切反映了前列腺癌骨转移患者中观察到的许多病理特征：肿瘤主要是成骨细胞，肿瘤在骨中的定植模式，形成硬化骨病变的单个肿瘤克隆，强大的血管生成，以及肿瘤的生存能力。虽然这些前列腺癌细胞不表达神经生长因子(NGF)，但初步数据表明，它们相关的基质细胞释放NGF，诱导原肌球蛋白受体激酶A(TrkA)+感觉神经纤维和交感神经纤维在荷瘤骨中戏剧性地萌发，这可能在推动前列腺癌引起的慢性骨痛中发挥主要作用。基于这些观察，我们假设：(1)从特定群体的基质细胞释放的NGF可以通过TrkA+诱导荷瘤骨中显著的出芽和神经瘤的形成，而不是TrkA-、感觉神经和交感神经纤维，这种病理重组的程度将预测前列腺痛行为的严重程度；(2)新长出的感觉和交感神经纤维具有独特的形态，并表达病理上高水平的前痛觉神经递质、通道/受体和丝裂原激活的蛋白激酶，这些在支配正常骨的神经纤维中从未观察到；(3)早期预防性应用抗NGF或抗TrkA可减轻肿瘤诱导的神经萌发、感觉神经纤维和交感神经纤维的痛前表型以及骨癌痛。相反，晚期应用抗NGF或抗TrkA只能部分逆转神经纤维的痛觉前表型，对已经发生的病理性发芽或神经瘤形成几乎没有影响。最重要的假设是，对NGF/TrkA通路的预防性阻断越早，病理性神经变化和疼痛就可以得到更有效的控制。如果正确，这个项目的数据可能会从根本上改变我们对前列腺癌引起的骨痛的理解和治疗。

DESCRIPTION (provided by applicant): Prostate cancer is unique among cancers as although it is highly metastatic, bone is frequently the only clinically detectable site of metastasis. Fortunately, patients with metastatic prostate cancer usually have a long survival time. Unfortunately, prostate metastasis to bone frequently causes a severe, chronic pain that reduces quality of life, functional status, and greatly increases health care utilization. The goals of this application are to understand the mechanisms that drive prostate cancer-induced bone pain and use this information to develop therapies that can better prevent and/or treat this chronic pain. In preliminary studies, we have refined a mouse model of prostate cancer bone pain so that it closely mirrors many of the pathological features observed in humans with prostate metastasis to bone in terms of: the tumor being primarily osteoblastic, the pattern of tumor colonization in bone, the individual tumor colonies forming sclerotic bone lesions, the robust vascularization, and viability of the tumor. While these prostate cancer cells do not express nerve growth factor (NGF), preliminary data suggest their associated stromal cells release NGF that induces dramatic sprouting of tropomyosin receptor kinase A (TrkA)+ sensory and sympathetic nerve fibers in the tumor-bearing bone that may play a major role in driving chronic prostate cancer-induced bone pain. Based on these observations, we hypothesize that: (1) NGF released from specific populations of stromal cells induces marked sprouting and neuroma formation by TrkA+, but not TrkA-, sensory and sympathetic nerve fibers in the tumor-bearing bone and that the extent of this pathological reorganization will predict the severity of prostate-induced pain behaviors; (2) newly sprouted sensory and sympathetic nerve fibers have a distinct morphology and express pathologically high levels of pro-algesic neurotransmitters, channels/receptors, and mitogen-activated protein kinases that are never observed in nerve fibers that innervate the normal bone; and (3) early preventive administration of anti-NGF or anti-TrkA attenuates the tumor-induced nerve sprouting, the pro-algesic phenotype of sensory and sympathetic nerve fibers, and bone cancer pain. In contrast, late administration of anti-NGF or anti-TrkA will only partially reverse the pro-algesic phenotype of the nerve fibers and have little or no effect on the pathological sprouting or neuroma formation that has already occurred. The overarching hypothesis is that the earlier preventive blockade of the NGF/TrkA pathway is initiated, the more effectively the pathological nerve changes and pain can be controlled. If correct, data from this project may fundamentally change our understanding and treatment of prostate cancer-induced bone pain.