A Novel Drug Target for Aggressive Prostate Cancer

侵袭性前列腺癌的新药物靶点

• 批准号: 10083680
• 负责人: Kerry L Burnstein
• 金额: --
• 依托单位: MIAMI VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10083680
• 关键词: Address; Androgen Receptor; Animal Model; Argipressin; Biological Specimen database; Bone Resorption; Bone Tissue; Bone remodeling; Cancer Patient; Castration; Cell Proliferation; Cells; Cessation of life; Chemotherapy-Oncologic Procedure; Clinic; Clinical; Clinical Trials; Data; Databases; Development; Disease; Disease Resistance; Distal; Dose; Ectopic Expression; Effectiveness; Evaluation; Foundations; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Gene Expression Profiling; Genetic Transcription; Growth; Human; In Vitro; Lesion; Ligands; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Medical Oncologist; Messenger RNA; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Modeling; Morbidity - disease rate; Mus; Neoplasm Metastasis; Oral; Osteoblasts; Osteoclasts; Osteogenesis; Pain; Pathological fracture; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Pre-Clinical Model; Principal Investigator; Prognosis; Property; Prostate Cancer therapy; Regulation; Research Personnel; Resistance; Role; Safety; Signal Pathway; Signal Transduction; Skeleton; Specimen; Testing; Therapeutic; Toxic effect; Translations; V1a vasopressin receptor; Variant; Vasoconstrictor Agents; Veterans; Work; Xenograft Model; androgen deprivation therapy; androgen sensitive; base; bone; bone cell; bone xenograft; cancer clinical trial; cancer diagnosis; castration resistant prostate cancer; cell motility; chemotherapy; docetaxel; efficacy evaluation; experience; improved; in vivo; in vivo Model; inhibitor/antagonist; man; men; migration; mouse model; new therapeutic target; novel; prevent; prostate cancer cell; prostate cancer progression; small molecule; small molecule inhibitor; soft tissue; standard of care; therapeutic target; transcriptome; tumor; tumor growth; vasoconstriction; virtual

Metastatic castration resistant prostate cancer (mCRPC) commonly occurs in the skeleton and soft tissues and is hallmarked by enhanced expression of androgen receptor (AR) and constitutively active AR variants such as AR-V7. Transcriptome analyses of AR-V7 in CRPC cells identified increased expression of the vasoconstrictor and G protein-coupled receptor, arginine vasopressin receptor-1a (AVPR1a). Analysis of public human databases revealed significantly higher levels of AVPR1a mRNA in human specimens of mCRPC compared to primary PC tumors. Selective depletion of AVPR1a decreased CRPC cell proliferation. Conversely, expression of AVPR1a in androgen dependent PC conferred castration resistant growth in vitro and in vivo. Consistent with a potential role of AVPR1a signaling in mCRPC, the physiologic ligand for AVPR1a, arginine vasopressin (AVP), stimulated CRPC cell migration and invasion. Most importantly, inhibition of AVPR1a using relcovaptan, a clinically safe, effective and orally available AVPR1a antagonist, resulted in decreased CRPC growth in two distinct in vivo xenograft models, one representing newly emergent CRPC and the other a model of late stage bone metastasis. In the latter model, relcovaptan also diminished mCRPC-stimulated formation of bone lesions in vivo. PC-induced bone remodeling is a major cause of pain and pathological fracture in men with mCRPC. Based on these preliminary results, this proposal will investigate the hypothesis that AVPR1a is a therapeutic target for the most deadly form of PC, metastatic disease. The objectives of this proposal are to delineate the mechanisms by which AVPR1a is regulated and drives mCRPC and to evaluate the therapeutic potential of a safe and effective AVPR1a antagonist in mCRPC. The following specific aims will be addressed: Aim 1. Dissect cross talk between AVPR1a and AR/AR-V7; Aim 2. Interrogate the role of AVPR1a in mCRPC invasion and early metastasis; Aim 3. Determine the role of AVPR1a in mCRPC late metastatic growth in the bone microenvironment. These objectives will assess relcovaptan in conjunction with standard of care androgen deprivation therapy and chemotherapy in robust CRPC animal models representing the continuum from early invasion to late metastatic growth. Even “optimal” chemotherapy regimens, often the last line of options for the medical oncologist in treating mCRPC, have limited efficacy and considerable toxicity. Compounds that can work in combination with lower dose chemotherapy are an urgent and unmet clinical need. AVPR1a antagonists such as relcovaptan may be useful not only in inhibiting progression and growth of mCRPC but also in preventing excessive osteoclast activity, bone resorption and pathological fracture associated with mCRPC. The prior examination of relcovaptan in human clinical trials (for non-cancer disorders) means that this compound can be more rapidly tested in mCRPC clinical trials because dose, safety and efficacy have already been established in humans. Thus, this project has the potential for very rapid translation to the clinic for the treatment of mCRPC.

转移性去势抵抗性前列腺癌（mCRPC）通常发生在骨骼和软组织中 其特点是雄激素受体 (AR) 表达增强和组成型活性 AR 变体 例如 CRPC 细胞中 AR-V7 的转录组分析发现，AR-V7 的表达增加。 血管收缩剂和 G 蛋白偶联受体、精氨酸加压素受体-1a (AVPR1a) 的分析。 公共人类数据库显示，人类样本中 AVPR1a mRNA 水平显着升高 与原发性 PC 肿瘤相比，mCRPC 的选择性缺失可降低 CRPC 细胞增殖。 离线时，雄激素依赖性 PC 中 AVPR1a 的表达赋予体外去势抗性生长 与 AVPR1a 信号在 mCRPC（mCRPC 的生理配体）中的潜在作用一致。 AVPR1a，精氨酸加压素 (AVP)，刺激 CRPC 细胞迁移和侵袭。 使用relcovaptan（一种临床安全、有效且口服的 AVPR1a 拮抗剂）抑制 AVPR1a， 导致两种不同的体内异种移植模型中 CRPC 生长减少，其中一种代表新出现的 CRPC 和另一个晚期骨转移模型中，relcovaptan 也减少了。 mCRPC 刺激体内骨损伤的形成，PC 诱导的骨重塑是疼痛的主要原因。 根据这些初步结果，该提案将在患有 mCRPC 的男性中进行治疗。 研究 AVPR1a 是最致命的 PC（转移性 PC）的治疗靶点的假设 该提案的目的是描述 AVPR1a 的调​​节和控制机制。 驱动 mCRPC 并评估安全有效的 AVPR1a 拮抗剂的治疗潜力 mCRPC 将解决以下具体目标： 目标 1. 剖析 AVPR1a 和 AVPR1a 之间的串扰。 AR/AR-V7；目标 2. 探究 AVPR1a 在 mCRPC 侵袭和早期转移中的作用；目标 3. 确定 AVPR1a 在骨微环境中 mCRPC 晚期转移生长中的作用。 评估瑞科伐普坦与标准护理雄激素剥夺疗法和化疗的结合 稳健的 CRPC 动物模型代表了从早期侵袭到晚期转移生长的连续过程。 “最佳”化疗方案，通常是肿瘤内科医师治疗 mCRPC 的最后选择， 可以与较低剂量联合使用的化合物具有有限的功效和相当大的毒性。 化疗是一种紧迫且未得到满足的临床需求，AVPR1a 拮抗剂（如 relcovaptan）可能有用。 不仅可以抑制 mCRPC 的进展和生长，还可以防止破骨细胞过度活性， 与 mCRPC 相关的骨吸收和病理性骨折。 人体临床试验（针对非癌症疾病）意味着可以更快速地测试该化合物 mCRPC 临床试验的剂量、安全性和有效性已在人体中确定。 该项目有可能非常快速地转化为临床治疗 mCRPC。