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、更有效的药物来治疗糖尿病 前列腺癌(PC)。雄激素受体[AR及其剪接变异体]和MNK激活eIF4E信号 促进PC的发展、进展和转移，并诱导对多种药物的耐药 毒品的问题。我们最近开发了临床候选药物Galoneone(GAL)，它通过多种途径干扰AR信号传导 作用机制(1)。GAL进入转移性去势患者的关键III期临床试验-- 肿瘤细胞表达剪接变异体AR-V7的耐药PC(MCRPC)(ARMOR3-SV)。然而，最近的 终止这项试验(由于试验设计缺陷)和所需的2550毫克/天高治疗剂量的GAL 强调需要进一步系统地改进，以便能够开发下一代GAL 低剂量下疗效增强、治疗指数高的类似物(NGGA)--预期给药 从而在所有阶段/形式的PC中实现更安全、更有效的治疗。在研究开发的过程中 NGGA在PC模型中对AR信号的调制(2)，我们发现GAL及其新的更有效的类似物 (VNPP414和VNPP433-3β)也有效地靶向致癌的真核蛋白翻译，通过调节 MNK-eIF4E轴(3)。这些化合物还通过降解Mnk1和2以及AS抑制致癌的peif4E。 这类物质也称为MNK降解剂(MNKDA)。此应用程序的目标是确定 同时靶向AR/AR-V7和MNK/eIF4E的NGGA、VNPP433-3型β的治疗作用 用于治疗各种形式的PC，包括转移性疾病。在初步研究中，Gal和我们的新线索 NGGA降解AR/AR-vs、Mnk1/2，抑制PSA的合成和分泌，阻断细胞周期进程， 人PC细胞在培养中的生长，诱导凋亡，并抑制细胞迁移、侵袭和可能的干细胞 细胞标记物和逆转上皮向间充质转化(EMT)的表达，提示直接 对肿瘤过程的抑制作用。此外，新的NGGA(单独和联合使用)也抑制了 耐半乳糖、苯扎鲁胺、多西紫杉醇和米托蒽醌的人PC细胞系的生长。重要的是，首字母 体内试验表明，VNPP433-3β(等摩尔剂量比GAL低7.53倍)显著抑制(84%) 与GAL，47%；p&lt；0.01)抗去势22Rv1异种移植瘤的生长，没有明显的宿主毒性。 基于这些强大的初步数据，我们假设我们的新型NGGA具有极好的倍数 作为单一药物具有理想的抗PC活性，当组合使用时可以协同作用(增加抗PC活性) FDA批准的个人电脑药物。在这项建议中，我们将通过3个全面和假设驱动的方式进行 具体目标，基础/转化性临床前研究，重点是主要的VNPP433-3β，目标是 了解针对PC的完整作用机制及其翻译潜力。圆满完成 拟议的研究将提供毒理学、药理学和机械学数据(包括生物标记物(S)) 识别)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.