Development of Next Generation Galeterone Analogs for Prostate Cancer Therapy

用于前列腺癌治疗的下一代 Galeterone 类似物的开发

基本信息

批准号：
10347315
负责人：
VINCENT Collins Ofuka NJAR
金额：
$ 63.93万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10347315
关键词：
Androgen Receptor Antineoplastic Agents Apoptosis Biological Availability Castration Cell Cycle Progression Clinical Clinical Research Code Data Development Disease Disease Resistance Docetaxel/Mitoxantrone Dose Drug Costs Drug Kinetics Drug Targeting Drug resistance Eukaryotic Initiation Factors FDA approved FRAP1 gene Goals Growth Human In Vitro Lead Length MAP Kinase Gene Malignant neoplasm of pancreas Malignant neoplasm of prostate Modality Modeling Molecular Molecular Mechanisms of Action Names Neoplasm Metastasis Neoplastic Processes New Agents Oncogenic Oncology Oral Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Pharmacotherapy Phase Phase III Clinical Trials Phosphotransferases Property Prostate Cancer therapy Protein Translation Pathway Proteins Quality of life RNA Splicing Resistance Safety Signal Pathway Signal Transduction Techniques Therapeutic Therapeutic Agents Therapeutic Index Time Toxic effect Toxicology Transitional Cell Variant advanced prostate cancer analog base biomarker identification castration resistant prostate cancer cell growth cell motility clinical candidate clinical development clinically relevant docetaxel drug development drug discovery drug production effective therapy enzalutamide epithelial to mesenchymal transition gain of function improved in vivo in vivo Model in vivo evaluation men neoplastic cell next generation novel novel strategies novel therapeutics pharmacokinetics and pharmacodynamics pre-clinical pre-clinical research prostate cancer cell prostate cancer cell line prostate cancer metastasis prostate cancer model research clinical testing stem stem cell biomarkers stem cells stem-like cell synergism therapeutically effective therapy resistant translational potential trial design tumor tumor xenograft

项目摘要

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.

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 的发展、进展和转移，此外还诱导对多种疾病的耐药性我们最近开发了临床候选药物 Galeterone (gal)，它通过多种方式破坏 AR 信号传导。 Gal 的作用机制 (1) 已进入针对转移性去势患者的关键 III 期临床试验。耐药PC（mCRPC）的肿瘤细胞表达剪接变体AR-V7（ARMOR3-SV）。终止该试验（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完善以实现下一代 gal 的开发预计在低剂量给药下具有增强功效和高治疗指数的类似物（NGGA）在研究过程中，为 PC 的所有阶段/形式提供更安全、更有效的治疗方法。 NGGA 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 VNPP433-3β）还可以通过调节致癌真核蛋白翻译来有效靶向 Mnk-eIF4E 轴 (3) 这些化合物还通过降解 Mnk1 和 2 来抑制致癌性 peIF4E。此类物质也称为 Mnk 降解剂 (MNKDA)。本申请的目的是确定。同时靶向 AR/AR-V7 和 Mnk/eIF4E 的先导 NGGA VNPP433-3β 的治疗潜力在初步研究中，gal 和我们的新先导药物可用于治疗所有形式的 PC，包括转移性疾病。 NGGAs 降解 AR/AR-Vs、Mnk1/2，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，诱导细胞凋亡，并抑制细胞迁移、侵袭和推定干细胞细胞标记物并逆转上皮间质转化（EMT）的表达，表明直接作用对肿瘤过程的抑制作用此外，新的NGGA（单独和组合）也具有抑制作用。半乳糖苷、恩杂鲁胺、多西紫杉醇和米托蒽醌耐药的人 PC 细胞系的生长。体内测试表明，VNPP433-3β（等摩尔剂量比 gal 低 7.53 倍）显着抑制（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，我们发现我们的新型 NGGA 具有极好的多重性作为单一药物具有理想的抗 PC 活性，联合使用时可产生协同作用（抗 PC 活性增加）在这项提案中，我们将通过 3 个全面且假设驱动的方法来进行 FDA 批准的 PC 药物。具体目标，基础/转化临床前研究，重点关注先导VNPP433-3β，目标是了解针对 PC 的完整作用机制及其转化潜力。拟议的研究将提供毒理学、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 研究和最终的临床开发。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

VNLG-152R and its deuterated analogs potently inhibit/repress triple/quadruple negative breast cancer of diverse racial origins in vitro and in vivo by upregulating E3 Ligase Synoviolin 1 (SYVN1) and inducing proteasomal degradation of MNK1/2.

DOI：
10.3389/fonc.2023.1240996
发表时间：
2023
期刊：
Frontiers in oncology
影响因子：
4.7
作者：
通讯作者：

Transcriptome profiling reveals that VNPP433-3β, the lead next-generation galeterone analog inhibits prostate cancer stem cells by downregulating epithelial-mesenchymal transition and stem cell markers.

DOI：
10.1002/mc.23406
发表时间：
2022-07
期刊：
Molecular carcinogenesis
影响因子：
4.6
作者：
通讯作者：

Prospects for Clinical Development of Stat5 Inhibitor IST5-002: High Transcriptomic Specificity in Prostate Cancer and Low Toxicity In Vivo.

DOI：
10.3390/cancers12113412
发表时间：
2020-11-18
期刊：
Cancers
影响因子：
5.2
作者：
Maranto C;Udhane V;Jia J;Verma R;Müller-Newen G;LaViolette PS;Pereckas M;Sabharwal L;Terhune S;Pattabiraman N;Njar VCO;Imig JD;Wang L;Nevalainen MT
通讯作者：
Nevalainen MT