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cast割抗性前列腺癌（MCRPC）通常发生在骨骼和软组织中 并以增强的雄激素受体（AR）和组成性活性AR变体的表达为标志 例如AR-V7。 AR-V7在CRPC细胞中的转录组分析确定了增加的表达 血管收缩剂和G蛋白偶联受体，精氨酸加压素受体1a（AVPR1A）。分析 公共人类数据库显示在人类标本中的Avpr1a mRNA水平明显更高 MCRPC与原发性PC肿瘤相比。 AVPR1A高级CRPC细胞增殖的选择性部署。 相反，AVPR1A在雄激素依赖性PC中的表达在体外会耐castration canstration抗性生长 和体内。与AVPR1A信号在MCRPC（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。最重要的是， 使用Relcovaptan抑制AVPR1A，这是一种临床安全，有效和口服的AVPR1A拮抗剂， 在两个不同的体内特征模型中导致CRPC增长的改善，一种代表新出现 CRPC和另一个晚期骨转移的模型。在后来的模型中，Relcovaptan也减少了 MCRPC刺激的体内骨病变的形成。 PC诱导的骨骼重塑是疼痛的主要原因 MCRPC男性的病理骨折。基于这些初步结果，该建议将 研究AVPR1A是最致命形式的PC转移性靶标的假设 疾病。该提案的目标是描述对Avpr1a受管制的机制，并 驱动MCRPC并评估安全有效的AVPR1A拮抗剂的治疗潜力 MCRPC。将解决以下具体目的：目标1。在AVPR1A和 AR/AR-V7;目标2。询问AVPR1A在MCRPC入侵和早期转移中的作用；目标3。确定 AVPR1A在骨微环境中MCRPC晚期转移性生长中的作用。这些对象会 评估Relcovaptan与护理标准的雄激素剥夺疗法和化学疗法一起评估 强大的CRPC动物模型，代表从早期侵袭到晚期转移性生长的连续体。甚至 “最佳”化学疗法方案，通常是医学肿瘤科医生治疗MCRPC的最后选择， 效率有限，毒性相当大。可以与较低剂量结合起作用的化合物 化学疗法是紧急且未满足的临床需求。 Avpr1a拮抗剂（例如Relcovaptan）可能有用 不仅在抑制MCRPC的进展和生长方面，而且还可以防止过量破骨细胞活性 与MCRPC相关的骨骼分辨率和病理断裂。先前检查Relcovaptan 人类临床试验（对于非癌症）意味着该化合物可以在 MCRPC临床试验是因为已经在人类中建立了剂量，安全性和效率。那，这个 项目有可能非常快速地转化为诊所的治疗MCRPC。