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: 10620273
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620273
• 关键词: Ablation; Acetates; Adrenal Glands; African American population; Androgens; Androstenediols; Androstenedione; Animal Model; Back; Bone Development; Bone Formation Stimulation; 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; Morbidity - disease rate; Mus; Neoplasm Metastasis; Operative Surgical Procedures; Osteoblasts; Osteogenesis; Osteosclerotic Lesion; Oxidoreductase; Pain; Pathologic; 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; comparison control; dehydroepiandrosterone; enzalutamide; humanized mouse; improved; intratumoral androgen; male; men; military veteran; mortality; mouse model; neoplastic cell; novel therapeutics; osteoblast proliferation; pain reduction; pharmacologic; 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 晚期前列腺癌与显著的发病率相关。内皮素-1(ET-1)是前列腺癌- 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送回前列腺。 癌细胞。初步数据出人意料地证明了消融ET-1和雄激素的作用 对于去势抵抗型前列腺癌(CRPC)患者，有必要在成骨细胞中使用该药物以减少骨病变的生长。 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 促进成骨细胞导向的前列腺癌在骨骼中的进展。 本研究的目的是探讨ET-1和雄激素对小鼠肿瘤负荷的影响。 前列腺癌动物模型骨转移的三个具体目标。目标1将检查以下因素的影响 去势、脱氢表雄酮替代联合乙酸乙酯阻断建立人源化前列腺动物模型 癌症骨转移。SCID小鼠将接受阉割或假手术，并使用ETAR治疗 拮抗剂齐博坦或车辆控制系统。脱氢表雄酮缓释片的抗癌作用 联合使用齐博坦和去势对前列腺癌骨骼病变的发展将进行测试。它是 预期脱氢表雄酮的治疗，在用乙酸乙酯阻滞剂治疗的去势小鼠中，将增加发育 和/或骨中前列腺癌病变的大小与未接受DHEA治疗的对照组小鼠相比。目标2将 检测Hsd3b7基因敲除对脱氢表雄酮治疗前列腺癌骨病变进展的影响 老鼠。推测Hsd3b7编码的蛋白与脱氢表雄酮的成骨细胞转化有关。 雄烯二酮，雄烯二醇和睾酮。预计Hsd3b7的敲除将否定 脱氢表雄酮对去势小鼠前列腺癌形成的影响。 目标3将确定联合使用ETAR阻滞剂和雄激素耗竭是否可以阻止骨骼的启动 损害，已建立的损害的进展，或两者兼而有之。阉割和Etar的结合 药物阻断减少骨转移模型小鼠骨骼病变的数量 而不是单独一人。减少骨骼所需的雄激素耗竭和Etar阻断的时机 肿瘤负担尚不清楚。雄性SCID小鼠接种肿瘤前将接受去势或假手术 细胞或在骨骼损伤已建立的时间点。预计这两家公司的组合 雄激素耗竭和Etar阻断将阻止已建立的 损伤。 ADT是男性转移性前列腺癌的标准治疗方法，但疾病进展为CRPC 而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 阻断ETAR可能只有在最大限度地阻断雄激素的情况下才有效。这些发现是由 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。

项目成果

Castration Determines the Efficacy of ETAR Blockade in a Mouse Model of Prostate Cancer Bone Metastasis.

去势决定了 ETAR 阻断在前列腺癌骨转移小鼠模型中的功效。

• DOI: 10.1210/en.2019-00261
• 发表时间: 2019
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Moon,HenryH;Clines,KatrinaL;Cooks,MarkA;Cialek,CharlotteA;Esvelt,MarianA;Clines,GregoryA
• 通讯作者: Clines,GregoryA

Osteoblasts Generate Testosterone From DHEA and Activate Androgen Signaling in Prostate Cancer Cells.

成骨细胞从DHEA产生睾丸激素并激活前列腺癌细胞中的雄激素信号。

• DOI: 10.1002/jbmr.4313
• 发表时间: 2021-08
• 期刊: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
• 作者: Moon HH;Clines KL;O'Day PJ;Al-Barghouthi BM;Farber EA;Farber CR;Auchus RJ;Clines GA
• 通讯作者: Clines GA