Development of Novel Targeted Therapy for Prostate Cancer

前列腺癌新型靶向治疗的开发

• 批准号: 8712901
• 负责人: David Gaul
• 金额: $ 22.5万
• 依托单位: SOPHIA BIOSCIENCE, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-24 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8712901
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; Acetylation; Affect; Androgen Antagonists; Androgen Receptor; Androgens; Antineoplastic Agents; Bicalutamide; Biochemical; Biodistribution; Brachytherapy; Breast; Cancer cell line; Castration; Cells; Clinical; Clinical Trials; Cold Therapy; Collection; Combined Modality Therapy; Cutaneous; DU145; Data; Dependency; Developed Countries; Development; Disease; Drug or chemical Tissue Distribution; Drug resistance; Early Diagnosis; Early treatment; Exhibits; External Beam Radiation Therapy; Flutamide; Foundations; Generations; Goals; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone deacetylase inhibition; Histones; Hormones; In Vitro; Investigational Drugs; Investigational New Drug Application; LNCaP; Lead; MCF7 cell; Malignant Neoplasms; Malignant neoplasm of prostate; Medical; Metastatic Prostate Cancer; Mission; Molecular; Mus; Neoplasm Metastasis; Nilutamide; PC3 cell line; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Phase; Problem Solving; Prodrugs; Prostate Cancer therapy; Proteins; Radiation therapy; Radical Prostatectomy; Refractory; Research; Resistance; Resistance development; Screening for Prostate Cancer; Solid Neoplasm; Staging; Stream; T-Cell Lymphoma; Technology; Testosterone; Toxic effect; Treatment Efficacy; Tubulin; Tumor Tissue; United States; Vorinostat; Zolinza; base; cancer cell; cancer diagnosis; cancer therapy; chemotherapy; cohort; common treatment; cost; cytotoxic; deprivation; design; falls; in vivo; interstitial; men; mouse model; novel; novel strategies; oncology; pharmacophore; preclinical evaluation; preclinical study; public health relevance; receptor binding; receptor expression; resistance mechanism; therapeutic enzyme; therapeutic target; tumor; tumor growth

DESCRIPTION (provided by applicant): Prostate cancer (PCa) is the most diagnosed cancer among men in developed countries including the United States with significant medical cost burdens. Tremendous advances have been made in PCa screening technologies, which allow early detection and treatment. Common treatment options include radical prostatectomy, external beam radiation therapy (RT) and interstitial RT (brachytherapy), cryotherapy, and androgen deprivation therapy (ADT). Despite these advances, more than a quarter million men still die globally from the disease every year due primarily to treatment-resistance and metastasis. The androgen receptor (AR) expression state is one of the key hallmarks of PCa sustenance and progression. ADT, the first-line treatment option for symptomatic metastatic PCa, starves tumor of growth-promoting androgen hormones such as testosterone. ADT drugs (called antiandrogens) in clinical use, either as monotherapy or combination therapy (with castration), include bicalutamide (Casodex"), nilutamide (Nilandron"), and flutamide (Eulexin"). In the early stage, PCas respond well to ADT and other available therapies. However, malignant cells that survive 2- 3 years will typically enter an antiandrogen-resistant (i.e. castration-resisant or hormone refractory) state and subsequently exhibit chemotherapy-resistance. This castration-resistant state is incurable. Therefore, there is an unmet medical need for increasingly selective and potent drugs to treat castration-resistant stage of PCa. The specific focus of the studies in this proposal is to explore the tumor AR expression state to affect a selective delivery of an independent anti-tumor chemotype, in this case histone deacetylase inhibitor (HDACi). Our choice of HDAC as a therapeutic target is informed by the fact that HDAC inhibition is a clinically validated anti-cancer strategy that is selectively cytotoxic to transfored cells. HDACi have stimulated huge excitement in oncology recently, with close to 500 clinical trials initiated to date, resulting in two clinically approved drugs, SAHA (Zolinza") and FK228 (Istodax"), for the treatment of cutaneous T-cell lymphoma. However, current HDACi have serious limitations resulting from poor biodistribution, including ineffectively low concentrations in solid tumors and off-target toxicity, which is hampering clinical progress. The proposed research will solve two problems of main stream cancer therapy agents - resistance development of antiandrogens and lack of tumor accumulation of HDAC inhibitors - to furnish a novel class of targeted agents with potential to positively impact prostate cancer treatment.

描述（由申请人提供）：前列腺癌（PCa）是发达国家（包括美国）男性中诊断最多的癌症，医疗费用负担沉重。前列腺癌筛查技术取得了巨大进步，可以早期发现和治疗。常见的治疗选择包括根治性直肠癌切除术、外束放射治疗（RT）和间质性RT（近距离放射治疗）、冷冻治疗和雄激素剥夺治疗（ADT）。尽管取得了这些进展，但全球每年仍有25万多男性死于该病，主要原因是治疗耐药性和转移。雄激素受体（AR）的表达状态是前列腺癌维持和发展的关键标志之一。ADT是症状性转移性PCa的一线治疗选择，可使肿瘤缺乏促生长雄激素（如睾酮）。临床使用的ADT药物（称为抗雄激素），无论是作为单一疗法还是联合疗法（与去势），包括比卡鲁胺（Casodex）、尼鲁米特（Nilandron）和氟替卡松（Eulexin）。在早期阶段，PCas对ADT和其他可用的治疗反应良好。然而，存活2- 3年的恶性细胞通常将进入抗雄激素抗性（即去势抵抗或激素难治性）状态，随后表现出化疗抗性。这种阉割抵抗状态是无法治愈的。因此，对于治疗去势抵抗期PCa的越来越多的选择性和有效的药物存在未满足的医学需求。该提案中研究的具体重点是探索肿瘤AR表达状态以影响独立抗肿瘤化学型的选择性递送，在这种情况下是组蛋白脱乙酰酶抑制剂（HDACi）。我们选择HDAC作为治疗靶点是因为HDAC抑制是一种临床验证的抗癌策略，对转化细胞具有选择性细胞毒性。HDACi最近在肿瘤学中引起了巨大的兴奋，迄今为止已经启动了近500项临床试验，产生了两种临床批准的药物SAHA（Zolinza”）和FK 228（Istodax”），用于治疗皮肤T细胞淋巴瘤。然而，目前的HDACi由于生物分布差而具有严重的局限性，包括无效的低浓度 在实体瘤和脱靶毒性，这是阻碍临床进展。该研究将解决主流癌症治疗药物的两个问题-抗雄激素的耐药性发展和HDAC抑制剂缺乏肿瘤积累-提供一类新的靶向药物，有可能对前列腺癌治疗产生积极影响。