Inhibitors of Oxidative Protein Folding For The Treatment of Cancer

胰腺导管腺癌(PDAC)是胰腺癌中最常见的一种。 最致命的癌症。低存活率在很大程度上是由于诊断为PDAC的晚期。 以及缺乏有效的治疗方法。这项研究计划的长期目标是发现新的治疗方法 治疗PDAC和其他不治之症癌症的方法和药物组合。以前的研究 由我们课题组鉴定出一类新的具有多种固体活性的蛋白质二硫键异构酶(PDI)抑制剂 以及包括PDAC在内的血液性癌症类型。PDI是新兴的肿瘤学目标，在 新合成蛋白质的正确折叠。PDI在各种肿瘤类型中过度表达，并且 有吸引力的肿瘤学靶点。在FDA批准的肿瘤药物的无偏见筛选中，我们发现了这一新类别 能显著提高组蛋白脱乙酰酶(HDAC)抑制剂的活性，其中以 在PDAC模型中观察到了协同作用。这项研究的具体目标是：(1)揭示 PDI和HDAC抑制剂在PDAC中显著协同作用的分子机制，(2) 用X射线结晶学解析新型PDI抑制剂与其靶标的结合，以及(3)证明 铅PDI抑制剂单独及与HDAC抑制剂联用的临床前抗癌活性 在PDAC的基因工程小鼠模型(GEMM)中。这些目标建立在明确的基础上，从 现有文献和强大的初步数据。这项工作是创新的，因为我们调查了活动和 一种新的候选药物和新的治疗组合治疗肺癌PDAC的机制 迫切需要新的治疗方法。我们期望这项工作将提供一个新的候选药物和 联合治疗方案治疗PDAC，提供了洞察一种新兴的可药性 肿瘤药物在PDI中的靶点，并揭示增强HDAC抑制剂活性的分子机制。

Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is one of the deadliest forms of cancer. Poor survival rates are largely due to the late stage at which PDAC is diagnosed and a lack of effective therapies. The long-term goal of this research program is to discover new therapeutic approaches and drug combinations for the treatment of PDAC and other incurable cancers. Previous studies by our group identified a new class of protein disulfide isomerase (PDI) inhibitor with activity in a variety of solid and hematological cancer types including PDAC. PDIs are emerging oncology targets that play a critical role in the proper folding of newly synthesized proteins. PDIs are overexpressed in a variety of tumor types and are attractive oncology targets. In an unbiased screen of FDA-approved oncology drugs, we found this new class of drug could dramatically enhance the activity of histone deacetylase (HDAC) inhibitors with the strongest synergy being observed in PDAC models. The specific objectives of this study are: (1) to uncover the molecular mechanism responsible for the remarkable synergy between PDI and HDAC inhibitors in PDAC, (2) to resolve binding of novel PDI inhibitors to their target using X-ray crystallography, and (3) to demonstrate the preclinical anti-cancer activity of lead PDI inhibitors as single agents and in combination with HDAC inhibitors in genetically engineered mouse models (GEMMs) of PDAC. These aims are built on clear rationale from the existing literature and strong preliminary data. This work is innovative because we investigate the activity and mechanism of a new drug candidate and new treatment combination for the treatment of PDAC, a cancer in desperate need of new therapies. It is our expectation that this work will deliver a new drug candidate and combination treatment regimen for the treatment of PDAC, provide insight into the druggability of an emerging cancer drug target in PDI, and uncover molecular mechanisms that enhance the activity of HDAC inhibitors.