Development of Novel Targeted Therapy for Prostate Cancer

描述(申请人提供)：前列腺癌(PCa)是包括美国在内的发达国家男性中诊断最多的癌症，医疗费用负担巨大。前列腺癌筛查技术已经取得了巨大的进步，可以及早发现和治疗。常见的治疗方法包括根治性前列腺切除术、体外放射治疗(RT)和间质放射治疗(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，但全球每年仍有超过25万男性死于这种疾病，主要原因是治疗耐药和转移。雄激素受体(AR)的表达状态是前列腺癌维持和发展的重要标志之一。ADT是治疗有症状的转移性前列腺癌的一线治疗方案，它使肿瘤缺乏促进生长的雄激素，如睾酮。临床上使用的ADT药物(称为抗雄激素)，无论是单一疗法还是联合疗法(去势)，包括比卡鲁胺(Casodex)、尼鲁胺(Nilandron)和氟他胺(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年的恶性细胞通常会进入抗雄激素耐药(即去势耐药或激素耐药)状态，随后表现出化疗耐药。这种抵抗阉割的状态是无法治愈的。因此，对于治疗去势抵抗期前列腺癌的药物，有越来越多的选择性和强效药物的医学需求尚未得到满足。这项研究的重点是探索肿瘤AR的表达状态对选择性传递一种独立的抗肿瘤化学类型的影响，在这种情况下是组蛋白去乙酰酶抑制物(HDACi)。我们选择HDAC作为治疗靶点是因为HDAC抑制是一种经过临床验证的抗癌策略，对转分化细胞具有选择性的细胞毒作用。HDACi最近在肿瘤学领域激起了巨大的兴奋，迄今已启动近500项临床试验，产生了两种临床批准的药物，SAHA(Zolinza)和FK228(Istodax)，用于治疗皮肤T细胞淋巴瘤。然而，由于生物分布不佳，目前的HDACi具有严重的局限性，包括低效的低浓度。 在实体肿瘤和靶外毒性方面，这正在阻碍临床进展。这项拟议的研究将解决主流癌症治疗药物的两个问题-抗雄激素耐药性的产生和缺乏HDAC抑制剂的肿瘤积聚-以提供一类新的靶向药物，具有积极影响前列腺癌治疗的潜力。

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.