Convergence of Endothelin-1 and Androgen Signaling in Prostate Cancer Bone Metastasis

前列腺癌骨转移中内皮素 1 和雄激素信号的融合

基本信息

批准号：
10455423
负责人：
GREGORY A CLINES
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10455423
关键词：
Ablation Acetates Adrenal Glands African American population Androgens Androstenediols Androstenedione Animal Model Back Bone Development Castration Cessation of life Clinical Clinical Trials Complication Cues Data Development Diagnosis Disease Disease Progression Drug Targeting Endothelin A Receptor Endothelin-1 Enzymes Fracture General Population Generations Goals Growth Human Hydroxysteroid Dehydrogenases Isoenzymes Knock-out Laboratories Lesion Malignant Bone Neoplasm Malignant Neoplasms Malignant neoplasm of prostate Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Metastatic to Morbidity - disease rate Mus Neoplasm Metastasis Operative Surgical Procedures Osteoblasts Osteogenesis Osteosclerotic Lesion Oxidoreductase Pain Pathologic Pharmacology Protein Isoforms Proteins Radiation therapy Reporting Research Residual state Role SCID Mice Signal Pathway Signal Transduction Site Skeleton Stanolone Steroids Testing Testosterone Tumor Burden Veterans Vietnam abiraterone advanced prostate cancer agent orange androgen deprivation therapy antagonist bone cancer diagnosis castration resistant prostate cancer catalyst dehydroepiandrosterone enzalutamide humanized mouse improved intratumoral androgen male men military veteran mortality mouse model neoplastic cell novel therapeutics osteoblast proliferation pain reduction prevent prostate cancer cell prostate cancer metastasis prostate cancer model prostate cancer progression prostate cancer risk resistance mechanism sham surgery skeletal spinal cord compression standard care

项目摘要

Prostate cancer is the most common deadly cancer of men. Bone metastasis is a painful complication of advanced prostate cancer associated with significant morbidity. Endothelin-1 (ET-1) is a prostate cancer- secreted factor that activates the osteoblast endothelin A receptor (ETAR) causing osteoblast proliferation and pathologic new bone formation. In turn, osteoblasts send chemotactic and growth cues back to the prostate cancer cells. Preliminary data have unexpectedly demonstrated that ablation of both ET-1 and androgen action in osteoblasts is necessary to reduce bone lesion growth in castrate-resistant prostate cancer (CRPC). Furthermore, osteoblast generation of active androgens from adrenal dehydroepiandrosterone (DHEA) further fuels osteoblast-directed prostate cancer progression in bone. The goals of this proposal are to investigate the actions of ET-1 and androgen on tumor burden in an animal model prostate cancer bone metastasis in three specific aims. Aim 1 will examine the effects of castration and DHEA replacement combined with ETAR blockade in a “humanized” animal model of prostate cancer bone metastasis. Scid mice will undergo castration or sham surgery, and treatment with the ETAR antagonist zibotentan or a vehicle control. The effects of sustained-release DHEA to negate the effects of combined zibotentan and castration on the development of prostate cancer skeletal lesions will be tested. It is expected that DHEA treatment, in castrated mice treated with ETAR blockade, will increase the development and/or size of prostate cancer lesions in bone compared to control mice not receiving DHEA. Aim 2 will examine the effects of Hsd3b7 knockout on the progression of prostate cancer bone lesions in DHEA-treated mice. It is hypothesized that the protein encoded by Hsd3b7 is responsible for osteoblast conversion of DHEA to androstenedione, and androstenediol to testosterone. It is expected that knockout of Hsd3b7 will negate the effects of DHEA on the development of prostate cancer lesions in castrated mice treated with ETAR blockade. Aim 3 will determine if combined ETAR blockade and androgen depletion prevents the initiation of skeletal lesions, the progression of established lesions, or both. The combination of castration and ETAR pharmacologic blockade reduced the number of skeletal lesions in a mouse model of bone metastasis compared to either alone. The timing of androgen depletion and ETAR blockade required to reduce skeletal tumor burden is unknown. Male scid mice will undergo castration or sham surgery before inoculation of tumor cells or at the point when skeletal lesions have been established. It is expected that the combination of androgen depletion and ETAR blockade will prevent both the initiation and the progression of established lesions. ADT is the standard treatment in men with metastatic prostate cancer, but disease progression to CRPC and bone metastases in most men mark the fatal form of the disease. The clinical implication of this research is that ETAR blockade may be effective only with maximal androgen blockade. These findings generated by this proposal will be a catalyst for clinical trials to reduce the morbidity and mortality of CRPC in veterans.

前列腺癌是男性最常见的致命癌症，骨转移是一种痛苦的并发症。与显着发病率相关的晚期前列腺癌（ET-1）是一种前列腺癌。激活成骨细胞内皮素 A 受体 (ETAR) 的分泌因子，导致成骨细胞增殖和病理性新骨形成反过来，成骨细胞将趋化和生长信号发送回前列腺。初步数据出人意料地证明，ET-1 和雄激素作用均被消除。成骨细胞中的维生素D对于减少去势抵抗性前列腺癌（CRPC）中骨病变的生长是必要的。此外，成骨细胞从肾上腺脱氢表雄酮（DHEA）进一步产生活性雄激素促进骨中成骨细胞定向的前列腺癌进展。该提案的目标是研究 ET-1 和雄激素对肿瘤负荷的作用动物模型癌症骨转移的三个具体目标是检查癌症骨转移的影响。在“人性化”前列腺动物模型中进行去势和 DHEA 替代结合 ETAR 阻断癌症骨转移的 Scid 小鼠将接受去势或假手术，并接受 ETAR 治疗。拮抗剂 zibotentan 或载体对照缓释 DHEA 的作用，以抵消 DHEA 的作用。结合zibotentan和去势对前列腺癌骨骼病变的发展进行了测试。预计 DHEA 治疗（用 ETAR 阻断治疗的去势小鼠）将促进发育与未接受 DHEA Aim 2 的对照小鼠相比，骨中前列腺癌病变的大小和/或大小。检查 Hsd3b7 敲除对 DHEA 治疗的前列腺癌骨病变进展的影响人们重新认识到，Hsd3b7 编码的蛋白质负责成骨细胞转化 DHEA。预计Hsd3b7的敲除将消除雄烯二酮和雄烯二醇。 DHEA 对接受 ETAR 阻断治疗的去势小鼠前列腺癌病变发展的影响。目标 3 将结合确定 ETAR 阻断和雄激素消耗是否会阻止骨骼肌的启动去势和 ETAR 的组合。药物阻断减少了骨转移小鼠模型中骨骼病变的数量与单独使用雄激素消耗和 ETAR 阻断的时间相比，以减少骨骼。肿瘤负荷未知。雄性 scid 小鼠在接种肿瘤之前将接受去势或假手术。细胞或在骨骼损伤已建立时的组合是预期的。雄激素耗竭和 ETAR 阻断将阻止已建立的疾病的发生和进展。病变。 ADT 是转移性前列腺癌男性的标准治疗方法，但疾病进展为 CRPC 大多数男性的骨转移标志着这种疾病的致命形式。这项研究的临床意义是。 ETAR 阻断可能仅在最大雄激素阻断的情况下才有效。该提案将成为降低退伍军人 CRPC 发病率和死亡率的临床试验的催化剂。