MTA1- targeted strategies for prostate cancer management

MTA1-前列腺癌治疗的靶向策略

• 批准号: 10228847
• 负责人: Anait S Levenson
• 金额: $ 3.79万
• 依托单位: LONG ISLAND UNIVERSITY BROOKLYN CAMPUS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228847
• 关键词: Binding Sites; Biological Availability; Blueberries; Cancer Patient; Cell Membrane Permeability; ChIP-seq; Chemoprevention; Chemopreventive Agent; Clinic; Clinical Trials; DNA Binding; Development; Diet; Disease Management; Drug Kinetics; Drug or chemical Tissue Distribution; Epigenetic Process; Evaluation; Event; Exhibits; Foundations; Future; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genome; Goals; Grapes; Half-Life; Health Care Costs; Human; Inflammation; Lead; Luciferases; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metastasis-associated protein; MicroRNAs; Modeling; Molecular; Neoplasm Metastasis; Nutritional; Oncogene Activation; PTEN gene; Patient observation; Patients; Personal Satisfaction; Pharmacy Students; Pharmacy facility; Phase; Play; Post-Translational Protein Processing; Pre-Clinical Model; Prevention strategy; Prognostic Marker; Property; Prostate; Prostatectomy; Protein p53; Protocols documentation; Quality of life; Reporter; Reporting; Research; Resveratrol; Retreatment; Role; Safety; Signal Transduction; Stilbenes; Testing; Therapeutic; Transcriptional Activation; Transcriptional Regulation; Transgenic Mice; Translating; age related; analog; anti-cancer; base; cancer chemoprevention; cancer initiation; cancer therapy; candidate marker; carcinogenicity; chromatin remodeling; clinical candidate; clinical development; college; combat; design; dietary chemoprevention; early detection biomarkers; efficacy clinical trial; graduate student; health science research; high risk; high risk men; high throughput technology; in vitro Assay; in vivo; inhibitor/antagonist; innovation; insight; lipophilicity; men; metabolic rate; mouse model; novel; overexpression; overtreatment; predictive marker; prevent; programs; prostate cancer model; prostate cancer prevention; prostate cancer progression; prostate cancer risk; response; sound; tumor; tumor growth; undergraduate student

ABSTRACT Nutritional chemoprevention is a promising approach for combating prostate cancer (PCa). Pterostilbene (PTER), a naturally occurring dimethoxy analog of resveratrol found in blueberries and grapes, has more potent pharmacokinetic properties defined by greater bioavailability and effective tissue distribution due to its longer half-life, reduced metabolic rate, lipophilicity and cell membrane-permeability. Therefore, PTER presents stronger candidacy for successful clinical development. We propose PTER as a lead natural agent for PCa chemoprevention. We have compelling evidence that PTER regulates at least two epigenetic networks in PCa: the epigenetic modifier MTA1 and microRNAs that target or are modulated by epigenetic regulators (Epi-miRNAs). Metastasis-associated protein 1 (MTA1) plays an important role in PCa by participating in chromatin remodeling and transcriptional regulation. Although MTA1 is known to be closely associated with aggressive PCa, we have evidence of MTA1 involvement in the early inflammation-related carcinogenic events leading to development of PCa, which presents MTA1 as a new chemopreventive target. Moreover, we found that dietary PTER is a potent inhibitor of MTA1 and MTA1-guided signaling. This study will test the hypothesis that PTER may prevent development of PCa, at least in part, through its ability to directly block MTA1 -mediated gene regulation and to modulate MTA1-associated Epi-miRNAs. Inhibiting MTA1-guided signaling could effectively delay and/or prevent the development and progression of PCa. We propose to: (1) Evaluate the MTA1-mediated chemopreventive efficacy of PTER in PCa mouse models. (2) Determine the mechanistic role of MTA1 as a transcriptional regulator in PCa. (3) Determine the role of PTER-regulated MTA1-associated Epi-miRs as chemopreventive and predictive biomarkers. The successful completion of this study will aid in the development of much needed preventive strategies based on natural epigenetic agents for the effective management of PCa. In the future, innovative therapeutic strategies can be developed including combination of stilbenes and other MTA1 inhibitors. Results of this study will also provide novel information on whether Epi-miRs could be developed as prognostic and predictive biomarkers of early stage PCa. Moreover, the results of our study will provide sound foundation for clinical trials, after which they can immediately be translated to the clinic for PCa chemoprevention with a major impact upon thousands of men at high risk. Finally, this R15 application offers excellent research exposure opportunities for undergraduate, professional pharmacy, and graduate students and will undeniably make significant contributions to the expansion of the Arnold &Marie Schwartz College of Pharmacy and Health Sciences research enterprise.

抽象的 营养化学预防是打击前列腺癌（PCA）的有前途的方法。翼展 （pter）是一种天然存在的蓝莓和葡萄中的白藜芦醇的二甲氧基类似物，具有更多 有效的药代动力学特性由更大的生物利用度和由于其有效组织分布而定义 更长的半衰期，代谢率降低，亲脂性和细胞膜 - 渗透率。因此，pter 为成功的临床开发提供了更强的候选资格。我们建议PTE作为铅天然代理 用于PCA化学预防。我们有令人信服的证据表明，PTE调节至少两个表观遗传学 PCA中的网络：靶向或由表观遗传学调节的表观遗传修饰剂MTA1和microRNA 监管机构（EPI-MIRNA）。 通过参与染色质，与转移相关的蛋白1（MTA1）在PCA中起重要作用 重塑和转录调节。尽管已知MTA1与侵略性密切相关 PCA，我们有MTA1参与早期炎症相关的致癌事件的证据 PCA的开发，该PCA将MTA1作为新的化学预防目标。而且，我们发现 饮食PTER是MTA1和MTA1引导的信号传导的有效抑制剂。这项研究将检验假设 这种PTE可以通过直接阻止MTA1的能力来阻止PCA的发展 - 介导的基因调节并调节MTA1相关的EPI-MIRNA。抑制MTA1引导 信号传导可以有效地延迟和/或防止PCA的发展和发展。我们建议 到：（1）评估PTE在PCA小鼠模型中PTER的MTA1介导的化学预防功效。 （2） 确定MTA1作为PCA中转录调节剂的机理作用。 （3）确定角色 由PTER调节的MTA1相关的Epi-Mirs作为化学预防和预测性生物标志物。这 这项研究的成功完成将有助于制定急需的预防策略 关于有效管理PCA的天然表观遗传剂。将来，创新的治疗 可以制定策略，包括硬骨和其他MTA1抑制剂的组合。结果 研究还将提供有关Epi-Mirs是否可以作为预后和 早期PCA的预测生物标志物。此外，我们的研究结果将为 临床试验，之后可以立即将其转化为PCA化学预防的诊所 对成千上万的高风险男人的重大影响。最后，此R15应用程序提供了出色的研究 本科生，专业药房和研究生的接触机会，不可否认 为扩大Arnold＆Marie Schwartz药学学院的扩张做出了重大贡献 健康科学研究企业。

项目成果

Grape Powder Supplementation Attenuates Prostate Neoplasia Associated with Pten Haploinsufficiency in Mice Fed High-Fat Diet.

• DOI: 10.1002/mnfr.202000326
• 发表时间: 2020-08
• 期刊: Molecular nutrition & food research
• 影响因子: 5.2
• 作者: Joshi T;Patel I;Kumar A;Donovan V;Levenson AS
• 通讯作者: Levenson AS

Dietary stilbenes as modulators of specific miRNAs in prostate cancer.

• DOI: 10.3389/fphar.2022.970280
• 发表时间: 2022
• 期刊: FRONTIERS IN PHARMACOLOGY
• 影响因子: 5.6
• 作者: Levenson, Anait S.

Gnetin C Intercepts MTA1-Associated Neoplastic Progression in Prostate Cancer.

• DOI: 10.3390/cancers14246038
• 发表时间: 2022-12-08
• 期刊: Cancers
• 影响因子: 5.2

Therapeutic Potential of Gnetin C in Prostate Cancer: A Pre-Clinical Study.

• DOI: 10.3390/nu12123631
• 发表时间: 2020-11-26
• 期刊: Nutrients
• 影响因子: 5.9
• 作者: Gadkari K;Kolhatkar U;Hemani R;Campanelli G;Cai Q;Kumar A;Levenson AS
• 通讯作者: Levenson AS

In Vitro Anticancer Properties of Table Grape Powder Extract (GPE) in Prostate Cancer.

鲜食葡萄粉提取物 (GPE) 在前列腺癌中的体外抗癌特性。

• DOI: 10.3390/nu10111804
• 发表时间: 2018
• 期刊: Nutrients
• 影响因子: 5.9
• 作者: Kumar,Avinash;D'silva,Melinee;Dholakia,Kshiti;Levenson,AnaitS
• 通讯作者: Levenson,AnaitS