OPPC targeting to improve pancreatic cancer treatment

OPPC 旨在改善胰腺癌治疗

• 批准号: 8295640
• 负责人: IRAIMOUDI S AYENE
• 金额: $ 8.25万
• 依托单位: LANKENAU INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-10 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8295640
• 关键词: Acute; Address; Advanced Malignant Neoplasm; Adverse effects; Affect; Area; Attenuated; Benign; Biochemical; Biological Models; Breeding; Cancer cell line; Cell Culture Techniques; Cell Death; Cell Survival; Cells; Cellular Stress; Chemicals; Clinic; Clinical; Cystinuria; Cytotoxic Chemotherapy; Disease; Engineering; Evaluation; Feeds; Functional disorder; Generations; Generic Drugs; Glucose; Glutathione; Glycolysis; Glycolysis Pathway; Growth; Homeostasis; Human; Hypoxia; Intellectual Property; Investigation; Knowledge; Legal patent; Malignant Neoplasms; Malignant neoplasm of pancreas; Metabolic; Metabolism; Modality; NADP; Neoplasm Metastasis; Normal Cell; Normal tissue morphology; Nutrient; Oxidative Stress; Oxygen; Pancreatic carcinoma; Patients; Pentose Phosphate Cycle Pathway; Pharmaceutical Preparations; Pilot Projects; Production; Property; Radiation therapy; Relapse; Relative (related person); Research; Resistance; Risk; Role; Route; Solid Neoplasm; Source; Stress; Structure; Sulfhydryl Compounds; Therapeutic; Time; Translations; Vascular blood supply; Work; Xenograft Model; attenuation; base; cancer cell; cancer therapy; chemotherapy; cost; cytotoxicity; disulfide compound; dithiol; drug candidate; hexokinase; high risk; improved; in vitro testing; in vivo; innovation; killings; mouse model; neoplastic cell; novel; novel therapeutics; pancreatic cancer cells; pancreatic neoplasm; pre-clinical; small molecule; stemness; therapeutic evaluation; tumor; tumor progression

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.

描述（由申请人提供）：攻击癌症中常见代谢畸变的治疗策略因其潜在的广泛应用而具有吸引力。糖酵解在癌症中被激活这一点得到了广泛的认可，但人们对糖酵解是否也是如此知之甚少 氧化戊糖磷酸循环（OPPC），糖酵解途径中己糖激酶下游的一个分支。OPPC负责产生许多NADPH还原活性，相对于正常细胞，癌细胞特别需要这种活性。在NADPH生成的水平上，对其在谷胱甘肽还原中的作用进行了大量的细胞生物化学研究，其中一些实验性治疗研究已经集中。然而，很少有研究选择性地减少NADPH作用本身在癌细胞中的治疗效果。在某种程度上，这种差距反映了缺乏一种癌症， 选择性探针，可以实现这一目标，我们在这个试点项目中解决。包括胰腺癌在内的所有癌症都迫切需要NADPH来维持在实体瘤中发现的高度氧化应激微环境中的不受调节的生长和存活。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。这些问题定义了癌细胞代谢知识的关键空白和新的治疗机会：众所周知，肿瘤的缺氧、葡萄糖饥饿区域对细胞毒性治疗具有抗性，其中NADPH的选择性衰减似乎可能杀死。在这个试点项目中，我们将评估新的化学探针，Hypoxin，它具有类似药物的性质，适合在体内评价。NADPH对维持细胞巯基稳态和细胞存活所需的谷胱甘肽水平至关重要。Hypoxin是由现有仿制药硫普罗宁的二聚体形式组成的二硫化物化合物，硫普罗宁目前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新颖的物质结构，代表了可申请专利的知识产权。在正常葡萄糖和正常氧化条件下（即，正常组织微环境），低氧代谢为硫普罗宁，硫普罗宁的临床药理学性质是众所周知的和良性的。在低氧、低葡萄糖条件下（即低氧肿瘤微环境），预测低氧通过竞争代谢应激癌细胞存活所需的NADPH驱动的适应机制网络来引起细胞死亡。将在胰腺癌细胞系和已建立的人胰腺癌异种移植模型中对Hypoxin的细胞毒性依赖于葡萄糖缺乏状态的预测进行体外和体内测试。这个重点突出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个简单的，但创新的专利保护的候选药物在Hypoxin，可以选择性地干扰NADPH水平的胰腺肿瘤，通常耐化疗。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，在及时和迅速出现的癌症代谢领域推进胰腺癌病理生理学的基础知识，而且有可能通过临床翻译利用这一知识。 独特药物样探针或其衍生物。考虑到知识产权保护、低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，在短时间内对候选药物进行患者治疗评价是一种现实的可能性。总之，该试点项目提供了一个高创新，高影响力的机会，以推进药物样探针的研究，不仅可以显着影响胰腺肿瘤代谢的基础知识，而且还可以快速开发，以改善患者这种致命疾病的治疗。 公共卫生相关性：非常需要有效的药物策略来根除转移性胰腺癌。该试点项目将在临床前评估一种名为Hypoxin的新型药物样二硫醇化合物的治疗潜力，该化合物可以选择性地靶向缺乏足够葡萄糖的细胞。低氧减弱NADPH水平，这损害了细胞巯基稳态，在葡萄糖剥夺条件下导致细胞死亡，因为氧化戊糖磷酸循环的活性不足，这对于在细胞应激条件下维持NADPH产生至关重要。我们假设，这种抗代谢化合物对于治疗晚期癌症（例如肿瘤微环境中的人类胰腺癌）特别有价值，这些微环境在不同程度上缺乏氧气和葡萄糖（由于为肿瘤提供血液的血液供应混乱）。该项目的意义和影响非常重要，因为这些肿瘤微环境是癌症“干性”特性、转移和治疗耐药性的臭名昭著的滋生地，这些特性、转移和治疗耐药性推动了临床进展、肿瘤复发和患者死亡。该项目提供了一个独特的机会，以探索胰腺癌细胞中具有基础和临床影响的特定代谢脆弱性，基于其潜在的治疗重要性，包括利用其他化疗和放疗方式。