METASTATIC PROSTATE CANCER-INDUCED BONE PAIN

转移性前列腺癌引起的骨痛

• 批准号: 8470571
• 负责人: PATRICK WILLIAM MANTYH
• 金额: $ 29.55万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8470571
• 关键词: Adverse effects; Analgesics; Appearance; Attenuated; Automobile Driving; Bone Marrow; Bone Pain; Calcitonin Gene-Related Peptide; Calcium Channel; Canis familiaris; Chronic; Data; Diagnosis; Disease; Dose-Limiting; Femur; Goals; Health Care Costs; Human; Immature Bone; Individual; Injection of therapeutic agent; Ion Channel; Lesion; MAPK14 gene; Malignant Bone Neoplasm; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of prostate; Marrow; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Modeling; Molecular; Monoclonal Antibodies; Morphology; Mus; NGFR Protein; Neoplasm Metastasis; Nerve; Nerve Fibers; Nerve Growth Factor 1; Nerve Growth Factors; Neuraxis; Neuroma; Neurotransmitter Receptor; Neurotransmitters; Non-Malignant; Non-Steroidal Anti-Inflammatory Agents; Opiates; Organ; Pain; Pathway interactions; Patients; Pattern; Periosteum; Peripheral; Phenotype; Phosphotransferases; Play; Population; Preventive; Prostate; Prostate carcinoma; Prostatic Neoplasms; Proteins; Quality of life; Radiation; Role; Sensory; Sensory Receptors; Severities; Site; Sodium Channel; Stromal Cells; TRPV1 gene; Testing; Time; Tropomyosin; Tyrosine 3-Monooxygenase; Vascularization; base; bone; cancer cell; cancer pain; chronic pain; clinically relevant; contactin; functional status; health care service utilization; male; mouse model; neoplastic cell; pain behavior; prevent; prostate cancer cell; receptor; therapy development; tumor

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.

描述（由申请人提供）：前列腺癌在癌症中是独一无二的，好像它是高度转移性的，但骨骼通常是唯一可检测到的转移部位。 幸运的是，前列腺癌患者的生存时间通常很长。 不幸的是，前列腺转移对骨骼经常引起严重的慢性疼痛，可降低生活质量，功能状态并大大增加医疗保健利用率。 该应用的目标是了解促进前列腺癌引起的骨痛的机制，并使用这些信息来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，我们已经完善了一种前列腺癌骨痛的小鼠模型，以便它在人类中观察到的许多病理特征，从前列腺转移到骨头的人体：肿瘤是骨细胞的肿瘤细胞模式，主要是骨骼中的肿瘤菌落的模式，骨骼中的肿瘤群体，单个肿瘤的肿瘤骨骨变性，良好的肿瘤性，肿瘤的肿瘤构成，依赖于肿瘤的肿瘤。 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，从而诱导肌霉素受体激酶A（TRKA）+感觉+感官和交感神经纤维的戏剧性发芽，在肿瘤骨骼中可能在可能在肿瘤的骨骼中起作用，从而在慢性病中起着重大作用。 基于这些观察，我们假设：（1）从特定的基质细胞群中释放的NGF会诱导TRKA+的明显发芽和神经瘤形成，但不是TRKA，但不是TRKA-，感觉和交感神经纤维，肿瘤骨骼中的感官和交感神经纤维，以及这种病理性重组的程度，预测了这种病理性的严重性的痛苦。 （2）新发芽的感觉和交感神经纤维具有独特的形态，并且在病理上表现出高水平的促性雌性神经递质，通道/受体和有丝分裂原激活的蛋白激酶，这些激酶在神经纤维中从未观察到，这些蛋白质激酶在神经纤维中从未观察到，这些蛋白质激酶会因正常的骨骼而产生。 （3）早期预防性抗NGF或抗Trka会减轻肿瘤诱导的神经发芽，感觉和交感神经纤维的促脂型表型以及骨癌疼痛。 相反，抗NGF或抗TRKA的晚期给药只会部分逆转神经纤维的促敏表型，并且对已经发生的病理发芽或神经瘤形成几乎没有影响。 总体假设是，启动了NGF/TRKA途径的较早预防阻断，可以控制病理神经变化和疼痛越有效。 如果正确，该项目的数据可能从根本上改变了我们对前列腺癌引起的骨痛的理解和治疗。