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Glutaminase I isoforms as personalized biomarkers of prostate cancer

谷氨酰胺酶 I 亚型作为前列腺癌的个性化生物标志物

基本信息

批准号：
10542372
负责人：
Jiaoti Huang
金额：
$ 39.49万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10542372
关键词：
Adenocarcinoma Aggressive behavior Anabolism Androgen Receptor Androgens Animal Model Biochemical Biological Markers Biopsy Cancer Patient Castrate sensitive prostate cancer Castration Cell Line Cells Cessation of life Clinic Clinical Compensation Data Dependence Disease Enzymes Glucose Glutaminase Glutamine Glycolysis Goals Heterogeneity Histologic Hormones Kidney Malignant Neoplasms Malignant neoplasm of prostate Metabolic Minority Molecular Neoplasm Metastasis Neuroendocrine Carcinoma Neuroendocrine Cell Nutrient Outcome Oxidative Phosphorylation Pathologic Patients Prediction of Response to Therapy Process Prognosis Prostate Cancer therapy Prostatectomy Protein Isoforms Public Health Receptor Inhibition Recurrence Resistance Sampling Specimen Starvation Testing Warburg Effect Work advanced disease advanced prostate cancer androgen sensitive cancer cell castration resistant prostate cancer cohort differential expression experience hormone therapy individual patient novel marker patient variability potential biomarker prostate cancer cell targeted treatment therapy resistant treatment response trend tumor

项目摘要

Abstract Prostate cancer (PCa) is a heterogeneous disease. Responses to therapy and prognosis vary significantly from patient to patient, and biomarkers that can predict therapy response and prognosis are urgently needed. In an attempt to identify metabolic mechanisms of hormonal therapy for PCa, we discovered that an important function of androgen receptor (AR) in advanced PCa is to upregulate the expression of glutaminase 1 (GLS1) which is critical for glutamine utilization by cancer cells to compensate for their inability to produce sufficient ATP and metabolic intermediates from glucose due to the Warburg effect. Hormonal therapy targeting AR inhibits GLS1 expression and glutamine utilization, starving cells to death. GLS1 has two isoforms, kidney-type glutaminase (KGA) and glutaminase C (GAC). Our work demonstrates that early stage, hormone-sensitive PCa mostly expresses kidney-type glutaminase (KGA), the weaker, AR-dependent GLS1 isoform, while late stage, therapy-resistant PCa mostly expresses the more potent and AR-independent glutaminase C (GAC). We have shown that this switch in the expression of GLS1 isoforms is a molecular basis for the important clinical phenomenon including tumors’ initial sensitivity to hormonal therapy and the eventual therapy resistance. Importantly, we also observed significant heterogeneity in the GLS1 isoform expression from case to case. For example, while the majority of hormone sensitive cancers expresses KGA, a minority expresses GAC. Similarly, while most cases of late stage PCa express GAC, a minority expresses KGA. The heterogeneous expression of GLS1 isoforms of different enzymatic activities by PCa of various disease stages was intriguing and prompted us to determine their possible correlations with the heterogeneous clinical outcomes observed in PCa patients. We will study the value of GLS1 isoforms as potential biomarkers with the hypothesis that tumors that predominantly express KGA respond better to hormonal therapy and have better prognosis while those that predominantly express GAC respond poorly to hormonal therapy and have worse prognosis. This hypothesis will be tested in large, highly valuable patient tumor cohorts of hormone sensitive prostate cancer and CRPC. Additionally we will test if differential expression of the GLA isoforms is associated with the two histologic types of PCa, adenocarcinoma that is AR dependent and usually has a protracted disease course vs small cell neuroendocrine carcinoma which is AR-independent and rapidly lethal.

摘要