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

 描述（由申请人提供）：胰腺癌（胰腺导管腺癌，PDAC）是预后较差的最致命的恶性疾病之一，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，开发新的治疗策略来治疗这种毁灭性的疾病是非常具有挑战性和意义的。PI3K-Akt-mTOR和MAPK通路在胰腺癌中高度失调。最近的研究还涉及这些途径的最下游信号传导组分eIF4F（特别是eIF4E-Mnk1/2轴），其在翻译水平上控制基因表达，朝向PDAC发展以及从头和获得性耐药。这一发现的重要性被靶向人类PDAC和实际上受这些功能障碍影响的其他癌症中的这种下游致癌联系的巨大治疗潜力所强调。在开发有效的雄激素受体降解剂（ARDA）以调节前列腺癌模型中的AR信号传导的研究过程中（1），我们发现这些新型ARDA还通过调节Mnk-eIF4E轴有效靶向致癌真核蛋白质翻译。我们注意到这些靶点与PDAC的发生、进展、转移和耐药性有关（2 - 5）。此外，通过靶向KRAS癌基因下游的Mnk-eIF4E，我们首次可以有效抑制KRAS的作用，KRAS是一种突变的癌基因，存在于约90%的PDAC肿瘤中（6）。我们还发现，这些ARDA不仅对前列腺癌细胞和肿瘤有效，而且它们也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galeterone和相关类似物）用于有效治疗PDAC的潜在用途。该提议的目的是通过阻断胰腺癌的临床前细胞培养物和动物模型中的Mnk-eIF4E活性来测试该假设，并且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前列腺癌患者的3期临床试验）及其更有效的类似物VNPP 414和VNPP 433 - 314，如果这些临床前研究显示出有希望的活性，则其应促进快速翻译。本论文的主要目标是：1）设计和开发具有很高应用前景的新型ARDA，VNPP 414和VNPP 433 - 333的实用合成方法。2)确定ARDA单药和与吉西他滨（PDAC治疗的选择性药物）联合用药的抗癌活性和作用机制。3)评估先导ADRA在PDAC异种移植物、原位和患者源性异种移植物中的体内抗肿瘤和抗转移疗效。该项目预计将产生新的信息，为未来广泛的机制研究奠定坚实的基础，以及先进的临床前开发和评估靶向Mnk-eIF4E信号传导的致癌潜力，作为通过其他NIH资助机制和可能与大/小制药公司合作的胰腺癌新的和改进的治疗手段。我们相信，拟议研究的结果将为使用多靶点ARDA作为治疗人类胰腺癌的新型治疗策略提供强有力的临床前概念验证。

 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.