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.

抽象的 转移性去势抵抗性前列腺癌（mCRPC）的治疗管理仍然是主要的临床治疗方法 局限性或局限于器官的前列腺癌可以通过手术或联合雄激素来治愈。 然而，一些患者会出现肿瘤复发。 男性由于 ADT 抗性克隆的发展而导致前列腺的致命性 侵袭性 mCRPC 经常会转移到远处器官，例如骨骼。 因此，迫切需要开发新的疗法来治愈。 晚期前列腺癌的侵袭性疾病的发展有利于多种“逃逸”的激活。 其中 AR 共激活剂如类固醇受体共激活剂-2 (SRC-2/NCOA2) 发挥着重要作用。 SRC-2 促进 CRPC 存活和快速转移的关键作用促进“代谢转换”。 晚期肿瘤使它们倾向于依赖“谷氨酰胺”来产生能量和 生存和转移生长所需的大分子的消融可抑制前列腺肿瘤。 体内存活和转移，表明这可能是治疗晚期患者的可行方法。 该提案的目标是 (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 转录反应以调节的上游信号事件 这种代谢重编程，以及（3）检查针对这种“代谢转换”的治疗益处 在 K22 颁奖期间，我希望能够找出分子联系。 细胞代谢和 mCRPC 中的致癌事件之间的关系，并检查靶向的潜在益处 该研究将提出新的见解来描述选择性损害前列腺癌的转移。 促进CRPC出现的代谢途径和潜在机制，这可能导致 发现用于早期检测临床重大疾病的潜在预后工具。

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