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Small-molecule therapy for metastatic prostate cancer

转移性前列腺癌的小分子治疗

基本信息

批准号：
9407585
负责人：
DAQING WU
金额：
$ 22.5万
依托单位：
METCURE THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9407585
关键词：
Acute American Androgen Receptor Animal Model Antineoplastic Agents Apoptosis Bilateral Biological Availability Bone Resorption Cancer Etiology Cancer cell line Castration Cells Cessation of life Colorado Disease Dose Drug Design Drug Kinetics Drug or chemical Tissue Distribution Dual-Energy X-Ray Absorptiometry Exhibits Flurbiprofen Generations Growth Healthcare High Pressure Liquid Chromatography Human Hybrids Image Immunohistochemistry Injectable Lead Malignant Neoplasms Malignant neoplasm of prostate Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Modeling Molecular Monitor Morbidity - disease rate Mus National Cancer Institute No-Observed-Adverse-Effect Level Nude Mice Patients Pharmaceutical Preparations Pharmacology Phase Plasma Pre-Clinical Model Process Production Property Prostate-Specific Antigen Rattus Relapse Resistance Rodent Model Roentgen Rays Route SCID Mice Safety Serum Serum Markers Signal Transduction Small Business Technology Transfer Research Solid Sprague-Dawley Rats Statistical Data Interpretation Tail Therapeutic Tissue Sample Toxic effect United States Universities Variant Veins Xenograft Model acute toxicity androgen deprivation therapy bone bone turnover cancer cell castration resistant prostate cancer clinical development clinically relevant cytotoxicity drug candidate effective therapy improved in vivo innovation intraperitoneal male men nanomolar novel pre-clinical response scale up skeletal small molecule survivorship tibia tumor tumor growth

项目摘要

Enzalutamide resistance is a major obstacle in the treatment of metastatic, castration-resistant prostate cancer (mCRPC). Recently we developed a small-molecule lead compound GH501 and demonstrated its potent activity against bone metastatic prostate cancer cells. In this Phase I STTR application, we hypothesize that GH501 is a novel lead compound with nanomolar potency against enzalutamide-resistant and bone metastatic prostate cancer. Two Aims are proposed. In Aim 1, we will synthesize high-purity GH501 and determine the acute toxicity, pharmacokinetics and in vivo bioavailability/distribution of GH501 in rodent models; in Aim 2, we will validate the in vivo efficacy of GH501 against mCRPC in clinically-relevant animal models. These studies will provide convincing rationale for us to continue the GH501 project at MetCure for further pre-clinical and clinical development. The project has important impact and translational potential in treating a lethal disease.

Enzalutamide耐药是治疗转移性去势抵抗性前列腺癌的主要障碍（mCRPC）。最近，我们开发了一种小分子先导化合物GH501，并证明了其有效的抗骨转移性前列腺癌细胞的活性。在第一阶段STTR申请中，我们假设 GH501是一种新型先导化合物，具有纳摩尔级抗Enzalutamide耐药和骨转移的效力前列腺癌提出了两个目标。在目标1中，我们将合成高纯度的GH501，并测定其 GH501在啮齿动物模型中的急性毒性、药代动力学和体内生物利用度/分布;在目标2中，我们将在临床相关动物模型中验证GH501对mCRPC的体内疗效。这些研究将为我们在MetCure继续GH501项目进行进一步的临床前研究提供令人信服的理由，临床发展。该项目在治疗致命疾病方面具有重要的影响和转化潜力。