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（由适用提供）：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，这是美国男性和女性在癌症相关死亡中的第四个最常见原因。由于胰腺癌是一个主要的公共卫生问题，因此开发了治疗这种毁灭性疾病的新治疗策略是高度挑战性和重要意义。 PI3K-AKT-MTOR和MAPK途径在胰腺癌中受到高度放松管制。最近的研究还实施了这些途径中最下游的信号传导成分，即EIF4F（特别是EIF4E-MNK1/2轴），该途径在转化水平上控制基因表达对PDAC发育，并从从头开始并获得抗药性。这一发现的重要性是由针对人类PDAC及其其他受这些功能障碍影响的其他癌症的下游致癌联系的巨大治疗潜力强调的。在开发潜在的雄激素受体降解剂（ARDA）的研究过程中，以调节前列腺癌模型中的AR信号传导（1），我们发现这些新型ARDA还通过调节MNK-EIF4E轴有效地靶向了肿瘤源性真核蛋白的翻译。我们注意到，这些靶标在PDAC的开发，进展，转移和耐药性（2-5）中已隐含。此外，通过靶向Kras Oncogene下游的MNK-EIF4E，我们可以首次有效地抑制Kras的作用，Kras的作用是突变的致癌基因，持续约90％的PDAC肿瘤（6）。我们还发现，这些ARDA不仅对前列腺癌细胞和肿瘤有效，而且也是有效的抗胰腺癌剂。我们的初步结果清楚地证明了ARDA（VN/124-1或Galeterone和相关类似物）的潜在用途。 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 poisoned to enter phase 3 clinical trials in castration-resistant prostate cancer patients) and its more efficient analogs VNPP414 and VNPP433-3ß，如果这些临床前研究表现出有希望的活性，则应促进快速翻译。将追求三个具体目标：1）设计和开发高度有希望的小说Ardas，VNPP414和VNPP433-3ß的实用综合。 2）确定抗癌活性，单独使用铅ARDA的作用机理，并与吉西他滨（PEMCITABINE（PDAC疗法的选举药物）结合使用）。 3）评估铅ADRA的体内抗肿瘤和抗转移性效率，在异种移植物，原位和患者衍生的PDAC的异种移植物中。预计该项目将产生新的信息，为将来的广泛机理研究奠定坚实的基础，以及对靶向MNK-EIF4E信号的致癌潜力的高级临床前开发以及评估，作为新颖和改善胰腺癌治疗的手段，通过其他NIH资助机制以及可能与大型/小型药品合作进行合作。我们认为，拟议的研究的结果将为使用多目标ARDA作为一种新型治疗策略在人类治疗胰腺癌方面提供强有力的临床前概念概念。