Targeting Metabolic Pathways in Bladder Cancer

靶向膀胱癌的代谢途径

• 批准号: 9556714
• 负责人: Piyush Agarwal
• 金额: $ 18.12万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9556714
• 关键词: Amino Acids; Animals; Bladder Neoplasm; Cancer cell line; Carbohydrates; Cell Line; Clinical; Data; Databases; Defect; Electron Transport; Fatty Acids; Fatty-acid synthase; Gene Deletion; Gene Expression; Genus Hippocampus; Glucose; Glutamine; Glycolysis; Growth; Hypoxia; Implant; Kidney Neoplasms; Lactase; Lactate Dehydrogenase; Malignant neoplasm of urinary bladder; Metabolic; Metabolic Pathway; Metabolism; Metformin; Oxidative Phosphorylation; Oxidoreductase; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Production; Stress; TP53 gene; Testing; Urothelial Cell; Warburg Effect; Work; Xenograft procedure; cancer cell; cell type; genetic signature; glucose uptake; inhibitor/antagonist; metabolic abnormality assessment; metabolic imaging; metabolic phenotype; metabolomics; tumor; tumor metabolism; uptake

We have preliminarily established that bladder cancer cell lines are uniquely sensitive to glutamine levels in their media and to a greater extent than glucose levels. Also, we have obtained metabolomic data on the metabolites for bladder cancer cell lines that differ in MTAP deletion status and p53 status. We are exploring certain pathways identified from this work as potentially targetable. We have begun to test the use of lactase dehydrogenase inhibitors developed by NCATS and Dr. Len Neckers in bladder cancer cell lines. We have also previously evaluated the use of fatty acid synthase inhibitors and shown that bladder cancer cell lines respond effectively to such inhibitors as well. Recently, we have successfully investigated the metabolic phenotype of 15 bladder cancer cell lines using the seahorse analyzer. We found that the majority of cell lines undergo oxidative phosphorylation and shift towards glycolysis when stressed under hypoxia through rates of OCR and ECR on the Seahorse analyzer. We have characterized their lactate production under various conditions as well. We have established that lactate dehydrogenase inhibitors can be quite effective in glycolytic cell lines and that metformin can be quite effective in oxidative phosphorylation-dependent cell lines. Moreover, treatment with metformin can induce sensitivity to lactate dehydrogenase inhibitors in oxidative phosphorylation-dependent cell lines. We are now attempting to silence lactate dehydrogenase and see if the effects are similar as seen with pharmacologic inhibition. We will then embark on animal studies which are currently hindered by limited staff and trial and error of drug administration.

我们首先确定膀胱癌细胞系对其培养基中的谷氨酰胺水平独特，并且比葡萄糖水平更大。此外，我们已经获得了有关MTAP缺失状态和p53状态不同的膀胱癌细胞系的代谢物的代谢组数据。我们正在探索从这项工作中确定的某些途径，这是可能的目标。我们已经开始测试NCAT和Len Neckers在膀胱癌细胞系中开发的乳糖酶脱氢酶抑制剂的使用。我们先前还评估了脂肪酸合酶抑制剂的使用，并表明膀胱癌细胞系也对这种抑制剂有效反应。最近，我们成功地使用了Seahorse分析仪研究了15个膀胱癌细胞系的代谢表型。我们发现，当通过海马分析仪上的OCR和ECR速率在低氧下压力时，大多数细胞系经历了氧化磷酸化，并向糖酵解转移。我们在各种条件下也表征了它们的乳酸产生。我们已经确定乳酸脱氢酶抑制剂在糖酵解细胞系中可能非常有效，并且二甲双胍在氧化磷酸化依赖性细胞系中可以非常有效。此外，用二甲双胍治疗可以诱导氧化磷酸化依赖性细胞系中对乳酸脱氢酶抑制剂的敏感性。我们现在正在尝试沉默乳酸脱氢酶，看看该作用是否与药理抑制作用相似。然后，我们将开始进行动物研究，这些动物研究目前受到有限的员工和药物管理试验和错误的阻碍。