INVESTIGATING THE ROLE OF THE TRANSCRIPTIONAL COREGULATOR SRC-2 IN CASTRATION RESISTANT PROSTATE CANCER

研究转录核心调节子 SRC-2 在去势抵抗性前列腺癌中的作用

• 批准号: 9763341
• 负责人: Subhamoy Dasgupta
• 金额: $ 20.67万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763341
• 关键词: Ablation; Acetylation; Aconitate Hydratase; Androgen Receptor; Automobile Driving; Biochemical; Bioenergetics; Biological Assay; Cancer Patient; Caring; ChIP-seq; Chromatin; Clinical; Clinical Trials; Data Set; Deacetylase; Development; Disease; Disease-Free Survival; Distant; Drops; Drug resistance; Early Diagnosis; Enzymes; Event; GRIP1 gene; Genetic; Genetic Transcription; Glutamine; Goals; Growth; Hyperactive behavior; Immunoprecipitation; Impairment; In Vitro; Isotopes; K22 Award; Lead; Link; Lipids; Malignant Neoplasms; Malignant neoplasm of prostate; Mass Spectrum Analysis; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Molecular; NCOA2 gene; Neoplasm Metastasis; Nutrient; Oncogenic; Operative Surgical Procedures; Organ; Pathway interactions; Patients; Pharmacology; Phenotype; Play; Prognostic Marker; Prostatic Neoplasms; Proteins; Radiation therapy; Recurrence; Resistance development; Role; Signal Pathway; Signal Transduction; Source; Steroid Receptors; Survival Rate; Therapeutic; Tracer; Translating; Work; alpha ketoglutarate; androgen deprivation therapy; base; bench to bedside; bone; cancer type; carboxylation; castration resistant prostate cancer; chemotherapy; clinically significant; fatty acid biosynthesis; genetic signature; genome-wide; in vivo; in vivo Model; inhibitor/antagonist; insight; lipid biosynthesis; macromolecule; men; mouse model; novel; novel therapeutics; overexpression; prognostic tool; prostate cancer metastasis; prostate cancer progression; response; targeted agent; therapeutic biomarker; therapy resistant; transcription factor; tumor; tumor metabolism; tumor progression

Abstract Therapeutic management of metastatic castration-resistant prostate cancer (mCRPC) remains a major clinical challenge. Localized or organ-confined prostate cancer can be cured by surgery, or a combination of androgen deprivation therapy (ADT), radiotherapy and/or chemotherapy. However, tumor recurrence occurs in some men due to the development of ADT-resistant clones which greatly contributes to the lethality of prostate cancer. Aggressive mCRPC frequently metastasizes to distant organs such as bone. As a result treatment becomes challenging and survival rate drops. Hence, there is an urgent need to develop new therapies to cure advanced prostate cancer. Development of aggressive disease is favored by activation of several `escape pathways' among which AR- coactivators such as steroid receptor coactivator-2 (SRC-2/NCOA2) plays a critical role promoting the survival and rapid metastasis of CRPC. SRC-2 promotes a “metabolic switch” in advanced tumors that predispose them to be dependent on `glutamine' to generate energy and macromolecules required for survival and metastatic growth. Ablation of SRC-2 suppresses prostate tumor survival and metastasis in vivo, indicating this may be a viable approach to treat advanced patients. So our objectives in this proposal are (1) to investigate the mechanisms that promote increased glutamine metabolism in tumors, (2) identify the upstream signaling events that stimulate SRC-2 transcriptional responses to regulate this metabolic reprogramming, and (3) examine the therapeutic benefits of targeting this `metabolic switch' to block cancer progression and metastasis. During the K22 award I expect to identify the molecular links between cellular metabolism and oncogenic events in mCRPC, and examine the potential benefits of targeting this pathway to selectively impair prostate cancer metastasis. The study will make novel insights depicting the altered metabolic pathways and underlying mechanisms promoting the emergence of CRPC, which may lead to the discovery of potential prognostic tools for early detection of clinically significant disease.

摘要 转移性去势抵抗性前列腺癌（mCRPC）的治疗管理仍然是一个主要的临床问题， 挑战.局限性或局限于器官的前列腺癌可以通过手术治愈，或联合使用雄激素 剥夺疗法（ADT）、放疗和/或化疗。然而，肿瘤复发发生在一些 由于ADT耐药克隆的发展，这极大地促进了前列腺的致命性， 癌侵袭性mCRPC经常转移到远处器官，如骨。因此，治疗 生存率下降。因此，迫切需要开发新的治疗方法来治愈 晚期前列腺癌侵袭性疾病的发展受到几种“逃逸”的激活的支持。 其中，AR辅激活因子如类固醇受体辅激活因子2（SRC-2/NCOA 2）起着重要的作用。 促进CRPC生存和快速转移的关键作用。SRC-2促进“代谢开关”， 晚期肿瘤，使其倾向于依赖“谷氨酰胺”产生能量， 生存和转移生长所需的大分子。SRC-2的消融抑制前列腺肿瘤 生存和转移的体内研究表明，这可能是一种可行的方法来治疗晚期患者。所以我们的 本研究的目的是（1）研究促进谷氨酰胺代谢增加的机制 在肿瘤中，（2）识别刺激SRC-2转录反应的上游信号事件，以调节 这种代谢重编程，（3）检查靶向这种“代谢开关”的治疗益处， 阻断癌症进展和转移。在K22奖期间，我希望能确定分子链， mCRPC中细胞代谢和致癌事件之间的关系，并检查靶向治疗的潜在益处 选择性地削弱前列腺癌的转移。这项研究将提出新的见解， 改变的代谢途径和促进CRPC出现的潜在机制，这可能导致 发现用于临床显著疾病的早期检测的潜在预后工具。

项目成果

Steroid receptor coactivator 3 (SRC-3/AIB1) is enriched and functional in mouse and human Tregs.

• DOI: 10.1038/s41598-021-82945-3
• 发表时间: 2021-02-09
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Nikolai BC;Jain P;Cardenas DL;York B;Feng Q;McKenna NJ;Dasgupta S;Lonard DM;O'Malley BW
• 通讯作者: O'Malley BW