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Altered Histidine Metabolism in Pancreatic Cancer: A Novel Metabolic Target to Enhance Gemcitabine Efficacy

胰腺癌中组氨酸代谢的改变：增强吉西他滨疗效的新代谢靶点

基本信息

批准号：
9893865
负责人：
Satyanarayana Rachagani
金额：
$ 16.94万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9893865
关键词：
Address Affect Amino Acids Ammonia Apoptosis Attenuated Biochemical Pathway Branched-Chain Amino Acids Cancer Etiology Cancer cell line Catabolism Cell Cycle Arrest Cell Death Cell Proliferation Cell Survival Cells Cessation of life Combined Modality Therapy Cytotoxic agent Data Dietary Intervention Disease Drug resistance Effectiveness Enzymes Essential Amino Acids Exhibits FRAP1 gene Fluorouracil Future Genetic Genetic Models Genus Hippocampus Glutamine Glycolysis Growth Histidine Histidine Ammonia-Lyase Histidine Metabolism Pathway Human Impairment In Vitro Incidence Individual Insulin-Like-Growth Factor I Receptor Leucovorin Malignant Neoplasms Malignant neoplasm of pancreas Metabolic Metabolic Diseases Metabolic Pathway Metabolic stress Metabolism Mitochondria Mus Neoplasm Metastasis Non-Insulin-Dependent Diabetes Mellitus Normal Cell Nutritional Obesity Organoids Outcome Pathogenesis Patients Pharmaceutical Preparations Pharmacology Plasma Play Production Proteins Research Resistance Resistance development Respiration Risk Role Serum Signal Transduction Supplementation Therapeutic Therapeutic Agents Tissues Toxic effect Treatment Efficacy Treatment Failure Tumor Volume United States amino acid metabolism anti-cancer cancer cell cancer therapy chemotherapeutic agent chemotherapy cytotoxic cytotoxicity effectiveness evaluation gemcitabine human tissue improved interest irinotecan metabolomics mortality mouse model new combination therapies novel novel therapeutics nutritional approach outcome forecast oxaliplatin pancreatic cancer cells pancreatic cancer model pancreatic cancer patients pancreatic neoplasm protein expression response symptomatic improvement tumor growth tumor metabolism uptake

项目摘要

Project Summary Pancreatic cancer (PC) is one of the most lethal malignancies in the United States with a rising incidence and mortality. Gemcitabine (GEM) has been the cornerstone for PC treatment but GEM resistance develops within weeks of chemotherapy initiation, resulting in only a modest impact on survival. Combining GEM with other chemotherapeutic drugs often leads to severe toxicity, without much improvement in survival. It is becoming clear that PC patients exhibit metabolic impairments that can impact their prognosis and survival. In fact, reprogrammed metabolism is a feature of cancer cells and there is an escalated interest in targeting metabolic pathways as a way to improve therapy response. To this end, glutamine metabolism has been widely studied to target cancer cell proliferation. However, the role of other amino acids in modulating PC pathogenesis is still unclear. Our preliminary data provide compelling evidence that serum His level is lower and tissue histidine ammonia lyase (HAL) expression is higher in mice exhibiting PC and human PC patients, compared to controls. Our studies in PC cell-lines showed that His induces cytotoxicity, with a concomitant increase in ammonia production. Moreover, His in combination with GEM exerted a greater cytotoxicity accompanied by a greater reduction in IGF- 1R/mTOR/S6K signaling compared to individual treatments. Therefore, we hypothesize that His and HAL are novel regulators of PC pathogenesis and that targeting His metabolism is a promising approach to enhance the anti-cancer effects of GEM. We will employ nutritional, pharmacological, and metabolic approaches to determine the role and mechanisms by which altered His metabolism regulates the response of PC to GEM therapy. We propose two specific aims: In Specific Aim 1, we will determine the mechanisms by which histidine in combination with gemcitabine exerts enhanced cytotoxic effects against PC cell-lines and PC organoids in vitro. In Specific Aim 2, we will evaluate the therapeutic efficacy of His in combination with GEM in orthotopic and genetic mouse models of PC. Altogether, the studies will uncover the role of His in modulating PC cell metabolism, identify potential mechanisms, and set the stage for future therapeutic discoveries.

项目总结