OPPC targeting to improve pancreatic cancer treatment

描述(由申请者提供)：治疗策略攻击癌症中常见的代谢异常很有吸引力，因为它们有潜在的广泛应用。人们普遍认识到，糖酵解在癌症中被激活，但人们对这种情况的了解要少得多。 对于氧化戊糖磷酸循环(OPPC)，是己糖激酶下游糖酵解途径的分叉。相对于正常细胞，OPPC负责产生癌细胞特别迫切需要的大部分NADPH还原活性。在NADPH生成的水平上，已经有相当多的细胞生化研究对其在谷胱甘肽还原中的作用进行了研究，其中一些实验性的治疗研究一直是重点。然而，关于选择性地减少NADPH本身在癌细胞中的作用以达到治疗效果的研究很少。在某种程度上，这一差距反映了癌症的缺失。 可以实现这一目标的选择性探索，我们在这个试点项目中谈到了这一点。包括胰腺癌在内的所有癌症都迫切需要NADPH，以在实体肿瘤中发现的高度氧化应激微环境中维持不受调控的生长和生存。然而，体内研究相对缺乏，包括开发可用的化学探针，或评估NADPH耗竭的直接或协同抗肿瘤作用。这些问题既定义了对癌细胞新陈代谢知识的关键差距，也定义了一个新的治疗机会：众所周知，肿瘤的低氧、葡萄糖饥饿区域对细胞毒治疗具有耐药性，在这种情况下，选择性减弱NADPH似乎可能会致命。在这个试点项目中，我们将评估新的化学探针--次泊辛，它具有适合体内评估的类药物特性。NADPH对于维持细胞内硫醇动态平衡和细胞存活所需的谷胱甘肽水平至关重要。次辛是一种二硫化物化合物，由现有仿制药硫普罗宁的二聚体组成，目前已被批准用于临床治疗胱氨酸尿症。虽然简单，但这种化合物是一种代表可申请专利的知识产权的新型物质结构。在正常的葡萄糖和正常的氧化条件下(即正常的组织微环境)，次泊辛被代谢成硫普罗宁，其临床药理性质是众所周知的和良性的。在低氧、低糖条件下(即低氧肿瘤微环境)，低氧素被预测通过竞争NADPH驱动的适应机制网络而导致细胞死亡，该网络是代谢应激的癌细胞生存所必需的。将在体外和活体胰腺癌细胞株以及已建立的人胰腺癌异种移植模型中测试次泊辛依赖于葡萄糖缺乏状态的细胞毒性的预测。这一高度集中的项目提供了高度的创新和临床影响。试点研究将集中在一种简单但创新的专利保护候选药物Hypooxin上，该药物可以选择性地干扰胰腺肿瘤中通常对化疗具有耐药性的NADPH水平。这项工作提供了一个低风险/高回报的前景，因为它提供了一个机会，在及时和快速出现的癌症代谢领域促进胰腺癌病理生理学的基本知识，但也有可能通过临床翻译 独特的类药物探针或其衍生物。考虑到知识产权保护、较低的商品成本以及基于化合物工程预期的低风险药理学和毒理学特征，在短时间内对患者进行候选药物的治疗评估是现实的可能性。总而言之，这一试点项目提供了一个高创新、高影响力的机会，以推进对类药物探针的研究，这种探针不仅可以显著影响胰腺肿瘤新陈代谢的基础知识，还可以快速利用它来改进这种致命疾病的患者治疗。 公共卫生相关性：迫切需要有效的药物策略来根除转移性胰腺癌。这项试点项目将在临床前评估一种名为Hypooxin的新型类药物二硫醇化合物的治疗潜力，该化合物可以选择性地针对缺乏足够葡萄糖的细胞。次辛能减弱NADPH水平，NADPH水平损害细胞硫醇动态平衡，导致细胞在缺糖条件下死亡，因为氧化戊糖磷酸循环活性不足，在细胞应激条件下维持NADPH的产生至关重要。我们推测，这种抗代谢化合物对于治疗晚期癌症特别有价值，例如在肿瘤微环境中的人胰腺癌，这些微环境不同程度地缺乏氧气和葡萄糖(由于供应肿瘤的血液供应紊乱)。这个项目的意义和影响是重要的，因为这些肿瘤微环境是癌症干细胞特性、转移和治疗耐药的臭名昭著的滋生场所，这些特性推动了临床进展、肿瘤复发和患者死亡。该项目提供了一个独特的机会，基于其潜在的治疗重要性，包括利用其他化疗和放射治疗方法，探索具有基础和临床影响的胰腺癌细胞中的特定代谢脆弱性。

DESCRIPTION (provided by applicant): Therapeutic strategies to attack common metabolic aberrations in cancer are appealing because of their potentially broad applications. It is widely appreciated that glycolysis is activated in cancer, but it is much less known that the same is true for the oxidative pentose phosphate cycle (OPPC), a fork in the glycolysis pathway downstream of hexokinase. OPPC is responsible for generating much of the NADPH reducing activity for which cancer cells have an especially acute need, relative to normal cells. At the level of NADPH generation, there has been considerable cell biochemical research into its role in glutathione reduction where some experimental therapeutic investigations have been focused. However, there has been little study of the effects of selectively reducing NADPH actions themselves in cancer cells for therapeutic benefit. In part, this gap reflects the lack of a cancer selective probe that can achieve this end, which we address in this pilot project. All cancers including pancreatic cancers have an acute need for NADPH to sustain unregulated growth and survival in the highly oxidative stressed microenvironments found in solid tumors. However, in vivo studies have been relatively lacking, including to develop a usable chemical probe or to evaluate direct or cooperative antitumor effects of NADPH depletion. These questions define both a key gap in knowledge of cancer cell metabolism and a novel therapeutic opportunity: hypoxic, glucose starved regions of tumors are well known to be resistant to cytotoxic therapy, where selective attenuation of NADPH seems likely to kill. In this pilot project, we will evaluate novel chemical probe, Hypoxin, which has drug-like properties suitable for in vivo evaluation. NADPH is crucial to sustain glutathione levels required for cellular thiol homeostasis and cell survival. Hypoxin is a disulfide compound comprised of a dimeric form of the existing generic drug Tiopronin, which is presently approved to treat cystinuria in clinic. While simple, this compound is a novel structure of matter that represents patentable intellectual property. Under normal glucose and normoxidative conditions (i.e., normal tissue microenvironment), Hypoxin is metabolized to Tiopronin, the clinical pharmacological properties of which are well known and benign. Under hypoxic, low glucose conditions (i.e. hypoxic tumor microenvironment), Hypoxin is predicted to elicit cell death by competing for an NADPH-driven network of adaptive mechanisms needed for the survival of metabolically stressed cancer cells. The prediction that the cytotoxicity of Hypoxin relies on a glucose-deficient state will be tested in vitro and in vivoin pancreatic cancer cell lines and established human xenograft models of pancreatic cancer. This tightly focused project offers a high degree of innovation and clinical impact. Pilot studies will focus on a simple but innovative patent-protected drug candidate in Hypoxin that can selectively interfere with NADPH levels in pancreatic tumors that are typically resistant to chemotherapy. The work offers a low-risk/high-payoff prospect in terms of the opportunity it offers to advance basic knowledge of pancreatic cancer pathophysiology in the timely and rapidly emerging area of cancer metabolism, but also the potential to exploit this knowledge by clinical translation of a unique drug-like probe or derivative thereof. Therapeutic evaluation of the candidate drug in patients is a realistic possibility in a short time-frame, given intellectual property protection, ow cost of goods, and low-risk pharmacological and toxicological profiles expected based on compound engineering. In summary, this pilot project offers a high-innovation, high-impact opportunity to advance studies of a drug-like probe that could not only significantly affect fundamental knowledge of pancreatic tumor metabolism but also permit its rapid exploitation to improve therapy of this deadly disease in patients. PUBLIC HEALTH RELEVANCE: Effective drug strategies to eradicate metastatic pancreatic cancers are greatly needed. This pilot project will preclinically evaluate the therapeutic potentia of a novel drug-like dithiol compound called Hypoxin that can selectively target cells deprived of sufficient glucose. Hypoxin attenuates NADPH levels which compromises cellular thiol homeostasis, causing cell death under glucose-deprived conditions because of insufficient activity of the oxidative pentose phosphate cycle that is vital to maintain NADPH production under conditions of cell stress. We hypothesize that this anti-metabolic compound will be particularly valuable to treat advanced cancers such as human pancreatic cancers in tumor microenvironments that are starved to various degrees for oxygen and glucose (due to the disorganized blood supply that feeds tumors). The significance and impact of this project is important, because these tumor microenvironments are notorious breeding grounds for cancer 'stemness' properties, metastasis and therapeutic resistance that drive clinical progression, tumor relapses and patient demise. This project offers a unique opportunity to probe a specific metabolic vulnerability in pancreatic cancer cells with fundamental and clinical impact, based on its potential therapeutic importance, including in leveraging other chemotherapeutic and radiotherapeutic modalities.