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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：
10361785
负责人：
Jiaoti Huang
金额：
$ 40.3万
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/10361785
关键词：
Adenocarcinoma Aggressive behavior Anabolism Androgen Receptor Androgens Animal Model Archives Biochemical Biological Markers Biopsy Cancer Patient Castration Cell Line Cells Cessation of life Clinic Clinical 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 Recurrence Resistance Sampling Specimen 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）是一种异质性疾病。对治疗的反应和预后差异很大患者之间的差异，迫切需要能够预测治疗反应和预后的生物标志物。在试图确定 PCa 激素治疗的代谢机制时，我们发现雄激素受体 (AR) 在晚期 PCa 中的一个重要功能是上调谷氨酰胺酶 1 (GLS1) 对于癌细胞利用谷氨酰胺补偿其代谢至关重要由于 Warburg 效应，无法从葡萄糖产生足够的 ATP 和代谢中间体。针对 AR 的激素疗法会抑制 GLS1 表达和谷氨酰胺利用，使细胞挨饿而死亡。 GLS1 有两种异构体：肾型谷氨酰胺酶 (KGA) 和谷氨酰胺酶 C (GAC)。我们的工作表明早期、激素敏感的 PCa 主要表达肾型谷氨酰胺酶 (KGA)，较弱的 AR 依赖性 GLS1 亚型，而晚期、治疗耐药的 PCa 大多数表达更多有效且不依赖 AR 的谷氨酰胺酶 C (GAC)。我们已经证明了 GLS1 表达式中的这个开关同种型是重要临床现象的分子基础，包括肿瘤对肿瘤的初始敏感性激素治疗和最终的治疗抵抗。重要的是，我们还观察到显着的异质性在不同情况下的 GLS1 同工型表达中。例如，虽然大多数激素敏感癌症表达KGA，少数表达GAC。同样，虽然大多数晚期 PCa 病例表示GAC，少数表示KGA。不同GLS1亚型的异质表达不同疾病阶段 PCa 的酶活性很有趣，促使我们确定它们与 PCa 患者中观察到的异质临床结果可能存在相关性。我们将学习 GLS1亚型作为潜在生物标志物的价值，假设主要表达的肿瘤 KGA 对激素治疗的反应更好，预后也更好，而那些主要表达 GAC 对激素治疗反应较差，预后较差。这个假设将在大范围内得到检验，非常有价值的激素敏感性前列腺癌和 CRPC 患者肿瘤队列。另外我们将测试 GLA 同工型的差异表达是否与 PCa 的两种组织学类型相关，与小细胞神经内分泌腺癌相比，AR 依赖性腺癌通常具有长期病程癌症是一种不依赖于 AR 且快速致死的癌症。