Development of Novel Targeted Therapeutic Agents for Castration Resistant Prostate Cancer

去势抵抗性前列腺癌新型靶向治疗药物的开发

• 批准号: 10337860
• 负责人: Chendil Damodaran
• 金额: $ 57.02万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-03 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10337860
• 关键词: Androgen Antagonists; Androgen Receptor; Androgens; Antineoplastic Agents; Apoptosis; Back; Biological Availability; Cancer Cell Growth; Cancer Etiology; Cell Proliferation; Cells; Clinical Research; Coupled; Dependence; Developed Countries; Development; Disease; Down-Regulation; Drug Kinetics; Drug or chemical Tissue Distribution; Drug resistance; Enzymes; Epigenetic Process; Event; Foundations; Functional disorder; Future; Generations; Goals; Growth; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; In Vitro; Investigational Drugs; Lead; Mainstreaming; Malignant neoplasm of prostate; Mediating; Modeling; Neoplasm Metastasis; Oral Administration; Outcome; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Pre-Clinical Model; Problem Solving; Property; Prostate Cancer therapy; RNA Splicing; Receptor Inhibition; Receptor Signaling; Regulation; Research; Resistance; Resistance development; Role; Screening for Prostate Cancer; Solid Neoplasm; Stimulus; Structure-Activity Relationship; Therapeutic; Toxic effect; Toxicology; Treatment Efficacy; Tumor Tissue; United States; Variant; Xenograft Model; Xenograft procedure; abiraterone; base; cancer diagnosis; cancer drug resistance; cancer therapy; castration resistant prostate cancer; clinical candidate; clinically relevant; cytotoxicity; effective therapy; enzalutamide; implantation; improved; in vivo Model; inhibitor; insight; member; men; nanomolar; neoplastic cell; new therapeutic target; novel; patient derived xenograft model; preclinical efficacy; prostate cancer cell; prostate cancer cell line; prostate cancer model; prostate cancer progression; rational design; receptor expression; resistance mechanism; small molecule; standard of care; targeted agent; targeted treatment; therapy resistant; tumor growth

PROJECT SUMMARY The overarching goal of this application is to develop a small molecule(s) that targets both the AR and epigenetic dysfunction for the treatment of castration-resistant prostate cancer (CRPC). Uncontrolled activation of androgen receptor (AR) is responsible for the development and progression of prostate cancer (PCa). Similarly, epigenetic events mediated through histone-modifying enzymes, such as histone deacetylases (HDACs), are essential to the regulation of AR signaling. Inhibition of HDACs suppress PCa cell proliferation through multiple mechanisms including AR degradation that results in the inhibition of AR signaling. Although, the current AR inhibitors (enzalutamide and abiraterone) are initially effective, these treatments eventually fail because of factors such as, AR-splice variants (AR-SVs) and AR responding to stimuli other than androgen. Systemic HDAC inhibitors (HDACi), despite promising preclinical efficacy, have shown sub-optimal effects in clinical studies of patients with CRPC. An effective way to control the emergence and treatment of CRPC is to develop small molecules that employ multiple mechanisms to either inhibit AR expression or promote its degradation. If there is no AR, there would be no AR signaling, regardless of whether or how much androgen or other stimuli of AR signaling are present in CRPC. The hypothesis is that rationally designed antiandrogen- equipped HDACi with enhanced bioavailability and potency will constitute a new generation of novel, targeted anti-PCa agents that will effectively inhibit the growth of both AR+ and AR-SV early stage PCa and CRPC by directly targeting AR through its degradation. The preliminary studies have furnished lead compounds (antiandrogen-HDACi) which engage with AR for selective tumor/tissue distribution, and potently inhibit AR, HDACs 1 and 6 for therapeutic impact. The proposed research will solve two problems of main-stream cancer therapy agents – resistance development of antiandrogens and lack of solid tumor efficacy of HDACi – to furnish a novel class of targeted agents with potential to positively impact CRPC treatment. The specific aims are: 1) Identify antiandrogen-HDACi with optimized pharmacokinetic (PK) properties and clean toxicity profile. 2) Investigate the mechanism of action and characterize the correlation between intracellular HDAC and AR inhibition in the promising antiandrogen-HDACi. 3) Determine the therapeutic efficacy of the promising antiandrogen-HDACi to inhibit CRPC growth in patient’s derived xenograft (PDX) and orthotopic implantation models via oral administration.

项目摘要 本申请的首要目标是开发一种靶向AR和AR的小分子。 表观遗传功能障碍用于去势抵抗性前列腺癌（CRPC）的治疗。不受控制的激活 雄激素受体（AR）的表达与前列腺癌（PCa）的发生、发展密切相关。 类似地，通过组蛋白修饰酶如组蛋白脱乙酰酶介导的表观遗传事件 （HDAC）对于AR信号传导的调节至关重要。HDAC的抑制抑制PCa细胞增殖 通过多种机制，包括导致AR信号传导抑制的AR降解。不过， 目前的AR抑制剂（恩杂鲁胺和阿比特龙）最初是有效的，这些治疗最终失败 这是由于诸如AR剪接变体（AR-SV）和AR对雄激素以外的刺激的反应等因素。 全身性HDAC抑制剂（HDACi），尽管具有有希望的临床前功效，但已经显示出在以下方面的次优效果： CRPC患者的临床研究。控制CRPC发生和治疗的有效方法是 开发采用多种机制抑制AR表达或促进其表达的小分子， 降解如果没有AR，就不会有AR信号，无论雄激素是否或有多少 或AR信号传导的其它刺激物存在于CRPC中。假设是合理设计的抗雄激素- 具有增强的生物利用度和效力的装备HDACi将构成新一代的新型靶向 抗PCa剂，其通过以下方式有效抑制AR+和AR-SV早期PCa和CRPC的生长： 通过其降解直接靶向AR。初步研究提供了先导化合物 （抗雄激素-HDACi），其与AR结合用于选择性肿瘤/组织分布，并有效抑制AR， HDAC 1和6的治疗影响。这项研究将解决主流癌症的两个问题 治疗药物-抗雄激素的耐药性发展和HDACi缺乏实体瘤疗效- 提供了一类新的靶向药物，有可能对CRPC治疗产生积极影响。具体目标 1）鉴定具有优化的药代动力学（PK）性质和干净的毒性特征的抗雄激素-HDACi。 2)研究作用机制并表征细胞内HDAC和AR之间的相关性 抑制有前途的抗雄激素-HDACi。3)确定有希望的治疗效果 抗雄激素-HDACi在患者来源的异种移植物（PDX）和原位植入中抑制CRPC生长 模型通过口服给药。