Development of Next Generation Galeterone Analogs for Prostate Cancer Therapy

该项目的总体长期目标是开发更安全、更有效的药物， 前列腺癌（PC）。雄激素受体[AR，包括其剪接变体]和Mnk激活的eIF4E信号传导 促进PC的发生、发展和转移，除了诱导对多种 毒品我们最近开发了临床候选药物galeterone（gal），它通过多种途径破坏AR信号传导。 作用机制（1）。Gal进展为转移性去势患者的关键III期临床试验- 耐药PC（mCRPC），其肿瘤细胞表达剪接变体AR-V7（ARMOR3-SV）。但近期 本试验终止（由于试验设计缺陷）和所需的2550 mg/天高治疗剂量gal 强调需要进一步系统地改进，以开发下一代gal 类似物（NGGA）在低剂量给药时具有增强的功效和高治疗指数 为PC的所有阶段/形式提供更安全、更有效的治疗。在学习过程中， NGGAs在PC模型中调节AR信号传导（2），我们发现gal及其新的更有效的类似物 （VNPP414和VNPP433 - 3 β）也通过调节致癌真核蛋白的翻译，有效地靶向致癌真核蛋白的翻译。 Mnk-eIF4E轴（3）。这些化合物还通过Mnk 1和2的降解抑制致癌peIF 4 E， 这些也被称为Mnk降解剂（MNKDA）。本申请的目的是确定 同时靶向AR/AR-V7和Mnk/eIF4 E前导NGGA，VNPP 433 - 3 β的治疗潜力 用于治疗所有形式的PC，包括转移性疾病。在初步研究中，加尔和我们的新线索 NGGAs降解AR/AR-Vs、Mnk 1/2，抑制PSA合成和分泌，阻断细胞周期进程， 人PC细胞在培养物中的生长，诱导凋亡，并抑制细胞迁移、侵袭和假定的干细胞增殖。 细胞标志物，逆转上皮间质转化（EMT）的表达，表明直接 对肿瘤过程的抑制作用。此外，新的NGGA（单独和组合）也抑制了 半乳糖、恩杂鲁胺、多西他赛和米托蒽醌耐药人PC细胞系的生长。重要的是，初始 体内试验显示，VNPP 433 - 3 β（等摩尔剂量比gal低7.53倍）显著抑制（84%） vs. gal，47%; p <0.01）去势抗性22Rv1异种移植肿瘤的生长，没有明显的宿主毒性。 基于这些强有力的初步数据，我们假设我们的新型NGGA具有极好的多重 作为单一药剂具有理想的抗PC活性，并且当组合时可以协同作用（具有增加的抗PC活性 FDA批准的PC药物。在本提案中，我们将通过3个全面和假设驱动的 具体目标，基础/转化临床前研究，重点关注VNPP 433 - 3 β，目标是 了解对PC及其翻译潜力的全部作用机制。成功完成 拟定研究将提供毒理学、药理学和机制数据（包括生物标志物） 鉴定），以支持先进的临床前IND使能研究和最终的临床开发。

The overall long-term goal of this project is the development of safer, more effective drugs for the treatment of prostate cancer (PC). Androgen receptor [AR, including its splice variants] and Mnk activated eIF4E signaling promote the development, progression, and metastasis of PC, in addition to induction of resistance to a variety of drugs. We recently developed clinical candidate galeterone (gal) which disrupts AR signaling via multiple mechanisms of action (1). Gal progressed into pivotal Phase III clinical trial in patients with metastatic castration- resistant PC (mCRPC) whose tumor cells express splice variant AR-V7 (ARMOR3-SV). However, the recent termination of this trial (due to trial design flaws) and the required 2550 mg/day high therapeutic dose of gal underscores the need to further systematic refinements to enable development of the next generation gal analogs (NGGAs) with enhanced efficacies and high therapeutic indices at low dose-administration expected to result in safer, more effective treatments across all stages/forms of PC. In the course of studies to develop NGGAs to modulate AR signaling in PC models (2), we discovered that gal and its new more efficacious analogs (VNPP414 and VNPP433-3β) also effectively target oncogenic eukaryotic protein translation, via modulation of Mnk-eIF4E axis (3). These compounds also suppress oncogenic peIF4E via degradation of Mnk1 and 2, and as such, are also referred to as Mnk degrading agents (MNKDAs). The objective of this application is to determine the therapeutic potential of lead NGGA, VNPP433-3β that simultaneously target both AR/AR-V7 and Mnk/eIF4E for the treatment of all forms of PC, including metastatic disease. In preliminary studies, gal and our new lead NGGAs degraded AR/AR-Vs, Mnk1/2, inhibited PSA synthesis and secretion, blocked cell cycle progression and growth of human PC cells in culture, induced apoptosis, and inhibited cell migration, invasion, and putative stem cell markers and reversed the expression of epithelial-to-mesenchymal transition (EMT), suggesting a direct inhibitory effect on the neoplastic process. In addition, the new NGGAs (alone and in combination) also inhibited the growth of gal-, enzalutamide-, docetaxel-, and mitoxantrone-resistant human PC cell lines. Importantly, initial in vivo testing showed that VNPP433-3β (at 7.53-fold lower equimolar dose than gal) markedly suppressed (84% vs. gal, 47%; p < 0.01) the growth of castration-resistant 22Rv1 xenograft tumors, with no apparent host toxicity. Based on these strong preliminary data, we hypothesize that our novel NGGAs possess superb multiple desirable anti-PC activities as single agents and can synergize (with increased anti-PC activity) when combined with FDA approved PC drugs. In this proposal, we will conduct, through 3 comprehensive and hypothesis-driven specific aims, basic/translational pre-clinical research, focusing on lead VNPP433-3β, with the goal to understand the full mechanisms of action against PC and its translational potential. Successful completion of the proposed studies will provide the toxicological, pharmacological and mechanistic data (including biomarker(s) identification) to support advanced preclinical IND-enabling studies and eventual clinical development.