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.
Our laboratory has discovered that the protein endothelin-1 modifies how testosterone influences bone remodeling and therefore the risk of fracture. This discovery has significant implications for osteoporosis and prostate cancer bone metastasis, two diseases that effect the male veteran population. Agent Orange exposure, common in Vietnam veterans, doubles the risk for prostate cancer and increases the risk of prostate cancer bone metastasis at initial diagnosis. African-Americans, who make up a higher percentage of veterans than the general population, are also at a substantially increased risk of prostate cancer. Veterans are more likely to have other serious coexisting conditions at diagnosis resulting in more treatment-related complications. This proposal is aimed at understanding how conditions such as hypogonadism and therapies utilized in veterans with advanced prostate cancer such as androgen deprivation therapy influence bone metastasis and osteoporosis-related fractures.
