Endothelin-1 and androgen in prostate cancer bone metastasis and bone health

内皮素-1 和雄激素在前列腺癌骨转移和骨健康中的作用

• 批准号: 8626156
• 负责人: GREGORY A CLINES
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8626156
• 关键词: African American; Aging; Amino Acids; Androgens; Animal Model; Architecture; Area; Blood Vessels; Bone Development; Bone remodeling; Castration; Characteristics; Clinical; Clinical Trials; Complex; Data; Diagnosis; Disease; Disease Resistance; Endothelin; Endothelin A Receptor; Endothelin-1; Exhibits; Female; Fracture; Future; Gender; General Population; Goals; Gonadal Steroid Hormones; Gonadal structure; Growth; Homeostasis; Hypogonadism; Innate Bone Remodeling; Investigation; Kidney; Laboratories; Lesion; Location; Malignant neoplasm of prostate; Metastatic Neoplasm to the Bone; Metastatic to; Modeling; Mus; Nature; Osteoblasts; Osteogenesis; Osteoporosis; Osteosclerosis; Osteosclerotic Lesion; Patients; Phenotype; Play; Population; Proteins; Resistance; Risk; Role; Shapes; Signal Pathway; Signal Transduction; Site; Skeleton; Sodium Chloride; Testing; Testosterone; Time; Tumor Angiogenesis; Tumor Burden; Tumor Expansion; Vascular Endothelium; Vasoconstrictor Agents; Vertebral column; Veterans; Vietnam; advanced disease; agent orange; angiogenesis; bone; bone health; bone strength; deprivation; improved; long bone; male; men; preclinical study; prostate cancer cell; prostate cancer model; public health relevance; response; skeletal; substantia spongiosa; tumor; vascular contributions

DESCRIPTION (provided by applicant): Endothelin-1 (ET-1) is a 21 amino acid potent vasoconstrictor and product of vascular endothelium. ET-1 is also a tumor-secreted factor that has a central role in osteoblast activation and the osteosclerotic response of prostate cancer metastatic to bone. Antagonists that block the activation of the endothelin A receptor (ETAR), located on osteoblasts in bone, reduce osteoblastic bone lesions in animal models of bone metastasis. ETAR antagonists also reduce the progression of prostate cancer bone metastasis in men with advanced disease. ET-1 plays a vital role in normal bone development and remodeling as well. Young mice with a targeted inactivation of ETAR in osteoblasts have reduced trabecular bone volume. This phenotype was limited to the appendicular skeleton, sparing cortical bone and the spine. ET-1 expression in bone was restricted to vascular endothelium and correlated with the skeletal locations effected by osteoblast ETAR inactivation. In older mice, osteoblast ETAR inactivation exhibited gender and sex steroid-specific differences. Osteoblast ETAR inactivation did not change the rate of appendicular or axial bone accrual in eugonadal or hypogonadal females. In males however, osteoblast ETAR inactivation amplified the expected changes in bone accrual with androgen-osteoblast ETAR inactivation resulted in higher appendicular bone accrual in gonad-intact males but lower bone accrual with hypogonadism. Since androgen deprivation therapy (ADT) is a standard mode of therapy in men with advance castrate-resistant prostate cancer, the direct consequences of combined therapy with ETAR blockade on bone metastasis and on normal bone homeostasis are unclear. The primary goals of this proposal are to examine the role of ET-1 in normal bone homeostasis and to investigate the cooperation of ET-1 with androgen to influence the bone microenvironment and promote prostate cancer bone metastasis. Aim 1 will examine the contribution of ET-1 secreted by vascular endothelium within the primary spongiosa on trabecular bone modeling and remodeling. This will be accomplished by studying the bone phenotype of mice with ET-1 inactivated in vascular endothelium. The combination of androgen deprivation in combination with vascular endothelial ET-1 inactivation will be tested to examine the interaction between endothelin and androgens during normal bone modeling. Aim 2 will test how the ETAR antagonist zibotentan combined with castration effects tumor expansion in bone, osteosclerosis and angiogenesis in a model of prostate cancer bone metastasis. These studies are particularly relevant since continued ADT in men with castrate-resistant prostate cancer has not been shown to improve survival but is currently being used in combination with ETAR blockade in ongoing clinical trials. Since ADT therapy is associated with a high fracture risk, a complementary preclinical study will examine the effects of combined ADT and zibotentan on normal bone remodeling and strength of bone unaffected by prostate cancer. Defining the origins and actions of ET-1 in bone represent a new area of investigation that adds to accumulating evidence of a vascular-bone connection. The newly defined interaction between androgen and endothelin signaling adds to the already complex nature of androgen action in bone. The results expected from this proposal will illuminate a new mechanism of androgen action in bone, and have important clinical implications since the future of prostate cancer bone metastasis targeted-therapy will likely include ETAR blockade.

描述（由申请人提供）： Endothelin-1 (ET-1) 是一种由 21 个氨基酸组成的强效血管收缩剂，是血管内皮的产物。 ET-1 也是一种肿瘤分泌因子，在成骨细胞活化和前列腺癌骨转移的骨硬化反应中起核心作用。阻断位于骨中成骨细胞上的内皮素 A 受体 (ETAR) 激活的拮抗剂，可以减少骨转移动物模型中的成骨细胞骨病变。 ETAR 拮抗剂还可以减缓晚期男性前列腺癌骨转移的进展。 ET-1 在正常骨骼发育和重塑中也起着至关重要的作用。在成骨细胞中靶向灭活 ETAR 的年轻小鼠的骨小梁体积减少。这种表型仅限于附肢骨骼，不影响皮质骨和脊柱。骨中的 ET-1 表达仅限于血管内皮，并与成骨细胞 ETAR 失活影响的骨骼位置相关。在老年小鼠中，成骨细胞 ETAR 失活表现出性别和性类固醇特异性差异。成骨细胞 ETAR 失活不会改变性腺正常或性腺功能减退女性的阑尾或轴骨生长率。然而，在男性中，成骨细胞 ETAR 失活放大了雄激素引起的骨生成的预期变化，成骨细胞 ETAR 失活导致性腺完整的男性中附肢骨生成较高，但性腺功能减退时骨生成较低。由于雄激素剥夺疗法 (ADT) 是晚期去势抵抗性前列腺癌男性的标准治疗方式，因此联合治疗与 ETAR 阻断对骨转移和正常骨稳态的直接影响尚不清楚。该提案的主要目标是研究ET-1在正常骨稳态中的作用，并研究ET-1与雄激素的配合影响骨微环境并促进前列腺癌骨转移。目标 1 将检查初级海绵体内血管内皮分泌的 ET-1 对小梁骨建模和重塑的贡献。这将通过研究血管内皮中 ET-1 失活的小鼠的骨表型来实现。将测试雄激素剥夺与血管内皮 ET-1 失活的组合，以检查正常骨建模过程中内皮素和雄激素之间的相互作用。目标 2 将测试 ETAR 拮抗剂 zibotentan 联合去势如何影响前列腺癌骨转移模型中骨肿瘤扩张、骨硬化和血管生成。这些研究特别重要，因为对于去势抵抗性前列腺癌男性来说，持续 ADT 尚未被证明可以提高生存率，但目前在正在进行的临床试验中与 ETAR 阻断联合使用。由于 ADT 治疗与高骨折风险相关，因此一项补充临床前研究将检查 ADT 和 zibotentan 联合使用对正常骨重塑和不受前列腺癌影响的骨强度的影响。定义 ET-1 在骨骼中的起源和作用代表了一个新的研究领域，增加了血管-骨骼连接证据的积累。新定义的雄激素和内皮素信号传导之间的相互作用增加了雄激素在骨中的作用本已复杂的性质。该提案的预期结果将阐明雄激素在骨中作用的新机制，并具有重要的临床意义，因为前列腺癌骨转移靶向治疗的未来可能包括 ETAR 阻断。