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

描述(由申请人提供)： 内皮素-1(ET-1)是一种由21个氨基酸组成的强效血管收缩因子，是血管内皮细胞的产物。ET-1也是一种肿瘤分泌因子，在成骨细胞激活和前列腺癌骨转移的骨硬化反应中起核心作用。拮抗剂阻断位于骨成骨细胞上的内皮素A受体(ETAR)的激活，减少骨转移动物模型中的成骨细胞性骨损伤。Etar拮抗剂还可以减少晚期疾病男性前列腺癌骨转移的进展。ET-1在正常的骨发育和重建过程中也起着重要作用。在成骨细胞中有针对性地灭活Etar的年轻小鼠减少了骨小梁体积。这种表型仅限于阑尾骨骼，皮质骨和脊柱除外。ET-1在骨中的表达仅限于血管内皮细胞，并与成骨细胞Etar失活所影响的骨骼部位相关。在老年小鼠中，成骨细胞Etar失活表现出性别和性别类固醇特异性的差异。成骨细胞Etar失活不会改变优性腺或性腺下腺女性的附属骨或轴骨的累积率。然而，在男性中，成骨细胞Etar失活放大了雄激素对骨积累的预期变化-成骨细胞Etar失活导致性腺完整的男性附件骨积累较高，而性腺功能低下的男性骨积累较低。由于雄激素剥夺疗法(ADT)是男性晚期去势抵抗前列腺癌的标准治疗模式，联合应用Etar阻滞剂对骨转移和正常骨稳态的直接影响尚不清楚。本研究的主要目的是研究ET-1在正常骨稳态中的作用，以及ET-1与雄激素的协同作用，从而影响骨微环境，促进前列腺癌的骨转移。目的1研究原发性海绵体内血管内皮细胞分泌的ET-1在骨小梁模型和重塑中的作用。这将通过研究ET-1在血管内皮细胞中失活的小鼠的骨表型来实现。在正常骨模型中，将测试雄激素剥夺与血管内皮细胞ET-1失活的组合，以检查内皮素和雄激素之间的相互作用。目的2将测试Etar拮抗剂齐伯坦联合去势对前列腺癌骨转移模型中肿瘤在骨中的扩张、骨硬化和血管生成的影响。这些研究特别重要，因为对患有去势耐药前列腺癌的男性持续的ADT并未被证明能提高生存率，但目前正在进行的临床试验中与ETAR阻滞剂联合使用。由于ADT治疗与高骨折风险相关，一项补充的临床前研究将检查联合使用ADT和齐博坦对正常骨重建和不受前列腺癌影响的骨强度的影响。确定ET-1在骨骼中的起源和作用代表了一个新的研究领域，它增加了血管与骨骼联系的积累证据。新定义的雄激素和内皮素信号之间的相互作用增加了雄激素在骨骼中本已复杂的作用性质。这项建议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，因为未来前列腺癌骨转移的靶向治疗可能包括Etar阻断。

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.