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:
- 金额:$ 40.3万
- 依托单位:
- 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:
- 关键词:AdenocarcinomaAggressive behaviorAnabolismAndrogen ReceptorAndrogensAnimal ModelArchivesBiochemicalBiological MarkersBiopsyCancer PatientCastrationCell LineCellsCessation of lifeClinicClinicalDataDependenceDiseaseEnzymesGlucoseGlutaminaseGlutamineGlycolysisGoalsHeterogeneityHistologicHormonesKidneyMalignant NeoplasmsMalignant neoplasm of prostateMetabolicMinorityMolecularNeoplasm MetastasisNeuroendocrine CarcinomaNeuroendocrine CellNutrientOutcomeOxidative PhosphorylationPathologicPatientsPrediction of Response to TherapyProcessPrognosisProstate Cancer therapyProstatectomyProtein IsoformsPublic HealthRecurrenceResistanceSamplingSpecimenTestingWarburg EffectWorkadvanced diseaseadvanced prostate cancerandrogen sensitivecancer cellcastration resistant prostate cancercohortdifferential expressionexperiencehormone therapyindividual patientnovel markerpatient variabilitypotential biomarkerprostate cancer celltargeted treatmenttherapy resistanttreatment responsetrendtumor
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。
项目成果
期刊论文数量(0)
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Jiaoti Huang其他文献
Jiaoti Huang的其他文献
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{{ truncateString('Jiaoti Huang', 18)}}的其他基金
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
- 批准号:
10542372 - 财政年份:2022
- 资助金额:
$ 40.3万 - 项目类别:
Role and targeting of PRMT5 in prostate cancer
PRMT5 在前列腺癌中的作用和靶向
- 批准号:
10162523 - 财政年份:2017
- 资助金额:
$ 40.3万 - 项目类别:
Histologic and Immunohistochemical Biomarkers for Heavily Treated Metastatic Prostate Cancer.
重度治疗的转移性前列腺癌的组织学和免疫组织化学生物标志物。
- 批准号:
9081228 - 财政年份:2016
- 资助金额:
$ 40.3万 - 项目类别:
Histologic and Immunohistochemical Biomarkers for Heavily Treated Metastatic Prostate Cancer.
重度治疗的转移性前列腺癌的组织学和免疫组织化学生物标志物。
- 批准号:
9305047 - 财政年份:2016
- 资助金额:
$ 40.3万 - 项目类别:
A novel strategy to identify prostate cancer biomarkers for patient management
识别前列腺癌生物标志物以进行患者管理的新策略
- 批准号:
8579184 - 财政年份:2013
- 资助金额:
$ 40.3万 - 项目类别:
A novel strategy to identify prostate cancer biomarkers for patient management
识别前列腺癌生物标志物以进行患者管理的新策略
- 批准号:
9063044 - 财政年份:2013
- 资助金额:
$ 40.3万 - 项目类别:
A novel strategy to identify prostate cancer biomarkers for patient management
识别前列腺癌生物标志物以进行患者管理的新策略
- 批准号:
8845176 - 财政年份:2013
- 资助金额:
$ 40.3万 - 项目类别:
A novel strategy to identify prostate cancer biomarkers for patient management
识别前列腺癌生物标志物以进行患者管理的新策略
- 批准号:
8681397 - 财政年份:2013
- 资助金额:
$ 40.3万 - 项目类别:
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