OPPC targeting to improve pancreatic cancer treatment

OPPC 旨在改善胰腺癌治疗

基本信息

批准号：
8508202
负责人：
GEORGE C PRENDERGAST
金额：
$ 7.76万
依托单位：
LANKENAU INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-10 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8508202
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 metabolism tumor microenvironment tumor progression

项目摘要

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.

描述（由申请人提供）：攻击癌症中常见代谢异常的治疗策略因其潜在的广泛应用而颇具吸引力。人们普遍认为糖酵解在癌症中被激活，但鲜为人知的是，糖酵解也是如此用于氧化戊糖磷酸循环 (OPPC)，己糖激酶下游糖酵解途径中的一个分叉。 OPPC 负责产生大部分 NADPH 还原活性，相对于正常细胞，癌细胞对 NADPH 的需求尤其迫切。在 NADPH 生成水平上，对其在谷胱甘肽还原中的作用进行了大量的细胞生化研究，其中一些实验性治疗研究已成为重点。然而，关于选择性减少 NADPH 本身在癌细胞中的作用以获得治疗效果的研究很少。在某种程度上，这种差距反映了癌症的缺乏可以实现这一目标的选择性探测，我们在这个试点项目中解决了这个问题。包括胰腺癌在内的所有癌症都迫切需要 NADPH 来维持实体瘤中高度氧化应激的微环境中不受调节的生长和生存。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 消耗的直接或协同抗肿瘤作用。这些问题既定义了癌细胞代谢知识中的一个关键差距，也定义了一个新的治疗机会：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抵抗力，而选择性减弱 NADPH 似乎可能会杀死这些区域。在这个试点项目中，我们将评估新型化学探针Hypoxin，它具有适合体内评估的类似药物的特性。 NADPH 对于维持细胞硫醇稳态和细胞存活所需的谷胱甘肽水平至关重要。 Hypoxin 是一种二硫化物化合物，由现有仿制药硫普罗宁的二聚体形式组成，目前已被批准用于临床治疗胱氨酸尿症。这种化合物虽然简单，但却是一种新颖的物质结构，代表着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），Hypoxin 代谢为硫普罗宁，其临床药理学特性是众所周知的且良性的。在缺氧、低葡萄糖条件下（即缺氧肿瘤微环境），Hypoxin 预计会通过竞争 NADPH 驱动的适应机制网络来引发细胞死亡，这些适应机制是代谢应激的癌细胞生存所需的。 Hypoxin 的细胞毒性依赖于葡萄糖缺乏状态的预测将在体外和体内胰腺癌细胞系中进行测试，并建立胰腺癌的人类异种移植模型。这个重点突出的项目提供了高度的创新和临床影响。试点研究将重点关注 Hypoxin 中一种简单但创新的受专利保护的候选药物，它可以选择性地干扰通常对化疗耐药的胰腺肿瘤中的 NADPH 水平。这项工作提供了低风险/高回报的前景，因为它提供了在及时且快速新兴的癌症代谢领域中推进胰腺癌病理生理学基础知识的机会，而且还具有通过临床转化来利用这些知识的潜力。一个独特的药物样探针或其衍生物。鉴于知识产权保护、商品成本低以及基于化合物工程预期的低风险药理学和毒理学特征，在短时间内对患者候选药物进行治疗评估是现实的可能性。总之，该试点项目提供了一个高创新、高影响力的机会来推进类药物探针的研究，这种探针不仅可以显着影响胰腺肿瘤代谢的基础知识，还可以快速利用它来改善这种致命疾病的治疗在患者中。