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

• 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
• 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

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， 与显著发病率相关的晚期前列腺癌。内皮素-1（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，引起成骨细胞增殖， 病理性新骨形成。反过来，成骨细胞将趋化和生长信号送回前列腺 癌细胞初步的数据出乎意料地表明，ET-1和雄激素作用的消除， 在成骨细胞中，减少去势抵抗性前列腺癌（CRPC）中骨病变生长是必要的。 此外，成骨细胞从肾上腺脱氢表雄酮（DHEA）产生活性雄激素进一步 促进骨中成骨细胞导向的前列腺癌进展。 本研究的目的是研究ET-1和雄激素对肿瘤负荷的作用， 动物模型前列腺癌骨转移的三个具体目标。目标1将研究 去势和DHEA替代联合ETAR阻断在前列腺“人源化”动物模型中的应用 癌症骨转移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。持续释放DHEA的效果，以抵消的影响， 将测试zibotentan和去势的组合对前列腺癌骨骼病变发展的影响。是 预期在用ETAR阻断剂治疗的去势小鼠中，DHEA治疗将增加 和/或骨中前列腺癌病变的大小。目标2将 检查Hsd 3b 7敲除对DHEA治疗的前列腺癌骨病变进展的影响， 小鼠推测由Hsd 3b 7编码的蛋白质负责DHEA的成骨细胞转化 雄烯二酮和雄烯二醇转化为睾酮。预期Hsd 3b 7的敲除将否定 在用ETAR阻断剂处理的去势小鼠中，DHEA对前列腺癌病变发展的影响。 目的3将确定ETAR阻断和雄激素耗竭联合使用是否可预防骨骼肌损伤的发生。 病变、已建立病变的进展或两者。去势和ETAR的结合 药物阻断减少了小鼠骨转移模型中骨骼病变的数量 相比之下，单独。减少骨骼肌损伤所需的雄激素耗竭和ETAR阻断的时机 肿瘤负荷未知。雄性scid小鼠在接种肿瘤前将进行去势或假手术 细胞或在骨骼病变已经建立的时候。预计， 雄激素耗竭和ETAR阻断将阻止已建立的 病变 ADT是转移性前列腺癌男性的标准治疗，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时有效。由此产生的这些发现 该提案将成为临床试验的催化剂，以降低退伍军人CRPC的发病率和死亡率。