Targeting Pancreatic Cancer with Novel Mnk-eIF4E and AR Modulating Agents

使用新型 Mnk-eIF4E 和 AR 调节剂靶向胰腺癌

基本信息

批准号：
8897035
负责人：
VINCENT Collins Ofuka NJAR
金额：
$ 21.53万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8897035
关键词：
Address Adenocarcinoma Cell Adopted Androgen Receptor Animal Model Antineoplastic Agents Area Back Biological Markers Cancer Etiology Cancer Model Cancer Patient Cell Culture Techniques Cell Line Cessation of life Characteristics Clinical Trials Data Development Disease Drug resistance Epithelial Erlotinib Exhibits Foundations Functional disorder Funding Mechanisms Future Gap Junctions Gene Expression Goals Human In Vitro Investigation KRAS2 gene Lead MAP Kinase Gene Malignant - descriptor Malignant Neoplasms Malignant neoplasm of pancreas Malignant neoplasm of prostate Metastatic Lesion Modeling Molecular Mutate Neoplasm Metastasis Oncogenes Oncogenic Outcome Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Phase II Clinical Trials Phase III Clinical Trials Pilot Projects Primary Neoplasm Prostate Cancer therapy Protein Translation Pathway Proteins Public Health Reporting Research Resistance Risk Route Safety Science Signal Transduction Solid Survival Rate Testing Therapeutic Time Translations Treatment Efficacy United States United States National Institutes of Health Woman Xenograft Model Xenograft procedure analog base cancer type castration resistant prostate cancer clinically relevant cost design effective therapy gemcitabine high risk human FRAP1 protein improved in vivo in vivo Model men novel novel therapeutics outcome forecast pre-clinical preclinical study prostate cancer cell prostate cancer model public health relevance resistance mechanism small molecule treatment strategy tumor

项目摘要

DESCRIPTION (provided by applicant): Pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) is one of the most lethal malignant diseases with worse prognosis and, it is the 4th most common cause of cancer-related deaths in both men and women in the United States. Because pancreatic cancer is a major public health concern, the development of new therapeutic strategies for the treatment of this devastating disease is highly challenging and significant. The PI3K-Akt-mTOR and MAPK pathways are highly deregulated in pancreatic cancer. Recent studies have also implicated the most downstream signaling component of these pathways, eIF4F (specifically, eIF4E-Mnk1/2 axis) that control gene expression at the translational level towards PDAC development and to de novo and acquired drug resistant. The significance of this finding is underscored by the tremendous therapeutic potential for targeting this downstream oncogenic nexus in human PDAC and indeed other cancers impacted by these dysfunctions. In the course of studies to develop potent androgen receptor degrading agents (ARDAs) to modulate AR signaling in prostate cancer models (1), we discovered that these novel ARDAs also effectively target oncogenic eukaryotic protein translation, via modulation of Mnk- eIF4E axis. We note that these targets have been implicated in the development, progression, metastasis and drug resistance of PDAC (2-5). In addition, by targeting Mnk-eIF4E which is downstream of KRAS oncogene, we could for the first time effectively suppress the action of KRAS, a mutated oncogene present ~90% of PDAC tumors (6). We also discovered that these ARDAs are not only effective against prostate cancer cells and tumors but they are also effective anti-pancreatic cancer agents. Our preliminary results clearly demonstrate a potential use of ARDAs (VN/124-1 or galeterone and related analogs) for effective treatment of PDAC. The objective of this proposal is to test this hypothesis by blocking both Mnk-eIF4E activity in preclinical cell culture and animal models of pancreatic cancer, and will do this by using our novel ARDAs, VN/124-1 (Galeterone or TOK-001; that is poised to enter phase 3 clinical trials in castration-resistant prostate cancer patients) and its more efficacious analogs VNPP414 and VNPP433-3ß, which should facilitate rapid translation if these preclinical studies show promising activity. Three specific aims will be pursued: 1) Design and develop practical synthesis of highly promising novel ARDAs, VNPP414 and VNPP433-3ß. 2) Determine the anti-cancer activities, mechanisms of action of lead ARDAs alone and in combination with gemcitabine (the elective drug for PDAC therapy). 3) To assess the in vivo anti-tumor and anti-metastatic efficacies of lead ADRAs in a xenograft, orthotopic and patient-derived xenograft of PDAC. This project is expected to generate new information to lay a solid foundation for future extensive mechanistic studies as well as advanced preclinical development and assessment of the oncogenic potential of targeting Mnk-eIF4E signaling as a means to novel and improved therapeutic for pancreatic cancer through other NIH funding mechanisms and possibly partnering with big/small pharmaceutical companies. We believe that the results from the proposed study will provide strong preclinical proof-of-concept for the use of multi-target ARDAs as a novel therapeutic strategy in the treatment of pancreatic cancer in humans.

描述（由申请人提供）：胰腺癌（胰腺导管腺癌，PDAC）是最致命的恶性疾病之一，预后较差，是美国男性和女性癌症相关死亡的第四大常见原因由于胰腺癌是一个主要的公共卫生问题，因此开发治疗这种破坏性疾病的新治疗策略极具挑战性且意义重大。最近的研究还表明，MAPK 通路在胰腺癌中高度失调，这些通路的最下游信号成分 eIF4F（特别是 eIF4E-Mnk1/2 轴）在翻译水平上控制 PDAC 发育以及从头到尾的基因表达。在研究过程中，针对人类 PDAC 以及受这些功能障碍影响的其他癌症的下游致癌关系的巨大治疗潜力强调了这一发现的重要性。我们发现，这些新型 ARDA 还可以通过调节 Mnk-eIF4E 轴，有效地靶向致癌真核蛋白翻译，从而调节前列腺癌模型中的 AR 信号传导。此外，通过靶向 KRAS 癌基因下游的 Mnk-eIF4E，我们可以研究 PDAC 的发生、进展、转移和耐药性。首次有效抑制 KRAS 的作用，KRAS 是一种突变癌基因，存在于约 90% 的 PDAC 肿瘤中 (6)。我们还发现这些 ARDA 不仅能有效对抗前列腺癌细胞和肿瘤，而且还是有效的抗胰腺癌药物。我们的初步结果清楚地证明了 ARDA（VN/124-1 或加莱特隆及相关类似物）有效治疗 PDAC 的潜在用途。本提案的目的是通过阻断这两种药物来检验这一假设。 Mnk-eIF4E 在临床前细胞培养和胰腺癌动物模型中的活性，并将通过使用我们的新型 ARDA、VN/124-1（Galeterone 或 TOK-001；准备进入去势抵抗性的 3 期临床试验）来实现这一点前列腺癌患者）及其更有效的类似物 VNPP414 和 VNPP433-3ß，如果这些临床前研究显示有希望的话，这应该有助于快速转化我们将追求三个具体目标：1) 设计和开发极具前景的新型 ARDA、VNPP414 和 VNPP433-3ß 的实用合成。 2) 确定先导 ARDA 单独以及与吉西他滨联合使用的抗癌活性和作用机制。 3) 评估先导 ADRA 在体内的抗肿瘤和抗转移功效PDAC 的异种移植、原位和患者来源的异种移植预计将产生新的信息，为未来广泛的机制研究以及以 Mnk-eIF4E 信号传导为手段的致癌潜力的先进临床前开发和评估奠定坚实的基础。通过其他 NIH 资助机制并可能与大/小型制药公司合作，开发新的和改进的胰腺癌治疗方法，我们相信拟议的研究结果将提供强有力的临床前研究。使用多靶点 ARDA 作为治疗人类胰腺癌的新型治疗策略的概念验证。