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.

抽象的前列腺癌（PCA）是一种异质疾病。对治疗和预后的反应差异很大从患者到患者，以及可以迫切需要预测治疗反应和提示的生物标志物。为了鉴定PCA激素疗法的代谢机制，我们发现高级PCA中雄激素受体（AR）的重要功能是更新谷氨酰胺1（GLS1）对于癌细胞利用谷氨酰胺的补偿至关重要由于Warburg效应，无法从葡萄糖产生足够的ATP和代谢中间体。靶向AR的激素疗法抑制GLS1表达和谷氨酰胺的利用，使细胞死亡。 GLS1具有两个同工型，肾型谷氨酰胺酶（KGA）和谷氨酰胺酶C（GAC）。我们的工作证明了早期的敏感PCA大多表达肾脏型谷氨酰胺酶（KGA），较弱的AR依赖性GLS1同工型，而后期耐药的PCA大多表达势和非抗AR依赖性谷氨酰胺酶C（GAC）。我们已经证明了GLS1表达中的此切换同工型是重要临床现象的分子基础，包括肿瘤对激素疗法和最终抗药性。重要的是，我们还观察到明显的异质性在GLS1中的同工型表达中。例如，大多数马龙敏感癌症表达KGA，少数族裔表示GAC。同样，虽然大多数晚期PCA案件 Express GAC，少数族裔kga。 GLS1同工型的异质表达不同 PCA的各种疾病阶段的酶活性很有趣，并促使我们确定它们与PCA患者观察到的异质临床结果的可能相关性。我们将学习 GLS1同工型作为潜在生物标志物的值，其假设主要表达肿瘤 KGA对荷尔蒙治疗的反应更好，并且预后更好，而那些主要表达的荷尔蒙治疗 GAC对荷尔蒙治疗的反应不佳，预后较差。该假设将大规模检验高度有价值的患者肿瘤队列的马酮敏感前列腺癌和CRPC。另外，我们会的测试GLA同工型的差异表达是否与PCA的两种组织学类型相关 AR依赖性腺癌，通常具有旷日持久的疾病病程与小细胞神经内分泌癌是非AR依赖性且迅速致死的癌。