Metabolic Rewiring Promotes AA PCa by Regulating Stromal-Epithelial Interaction

代谢重新布线通过调节间质-上皮相互作用促进 AA PCa

• 批准号: 10652987
• 负责人: Ganesh S Palapattu
• 金额: $ 37.18万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10652987
• 关键词: 6-Phosphofructo-2-kinase; Actins; Address; Adenosine; African American; African ancestry; American; Benign; Biochemical; Biochemical Markers; Bioinformatics; Biological; Biological Assay; Biological Markers; Biological Process; Biometry; CD44 gene; Cancer Biology; Cancer Patient; Carbon; Cells; Cellular Metabolic Process; Clinical; Clinical Management; Collagen; Collection; Data; Development; Diagnostic; Drug Targeting; Enzymes; Epidemiology; Epithelial-Stromal Communication; European; Foundations; Fructose; Future; Genes; Glean; Glucose; Glycolysis; In Vitro; Incidence; Inosine; Knowledge; Link; Malignant neoplasm of prostate; Mass Spectrum Analysis; Measures; Mediator; Metabolic; Metabolic Marker; Metabolism; Microarray Analysis; NADP; Operative Surgical Procedures; Organ; Pathologic; Pathology; Pathway interactions; Patients; Pentosephosphate Pathway; Phenotype; Plasma; Production; Property; Prostate; Prostatectomy; Purine Nucleotides; Race; Recurrence; Recurrent Malignant Neoplasm; Regulation; Research; Risk; Role; Route; Sampling; Science; Smooth Muscle; Stromal Cells; Techniques; Tenascin; Testing; Therapeutic; Tissue Microarray; Tissues; Training; Translating; Tumor Cell Migration; Tumor Promotion; Urine; adenosine deaminase; arm; biomarker panel; cancer health disparity; cancer recurrence; candidate identification; case control; clinical predictors; epidemiologic data; follow-up; health disparity; in vivo; insight; men; metabolome; metabolomics; novel; nucleotide metabolism; overexpression; predictive marker; prognostic; prostate cancer cell; prostate cancer cell line; prostate cancer model; small molecule; therapeutic target; tumor; tumor metabolism; tumor microenvironment; tumor progression

The long-term objective of our research plan is to reduce the disproportionate effects of prostate cancer on African American men. In this application, we have used the technique of metabolomic profiling to uncover underlying biochemical differences between prostate cancers of African American and European American origin. Metabolomics describes the science of quantifying the levels of metabolites (e.g., small molecules) that are the byproducts of cellular metabolism. That is to say, in this kind of analysis we are measuring the biochemical entities (or metabolites) that are produced by the functional machinery of the cell. With knowledge of the identity of specific metabolites we can infer the biological processes that produced them, thus gaining insight into a cell’s metabolism. Given this, a guiding principle of application is that unique biochemical differences exist between prostate cancers of African American and European American origin and that these differences can influence the tumors and their surrounding cells termed stroma such that together they can promote the progression of the tumors. Since African American prostate cancer grow and progress more rapidly than European American tumors, our studies will potentially address some of the causes underlying prostate cancer health disparity. In addition, it will also build a first-of-its-kind biomarker panel that can predict cancer recurrence in ancestry verified African American men with prostate cancer. In this proposal, we will i) identify the biochemical mechanism that drives elevated levels of inosine in African American Prostate Cancer, ii) evaluate the function of elevated inosine in making African American tumors aggressive and invoke tumor promoting properties in the surrounding stromal cells and iii) develop plasma based metabolic markers for biochemical recurrence in African American men. At the conclusion of this study, we will have developed a racially derived metabolomic model for prostate cancer as well as identified candidate pathways for future drug targeting. We would have also built a proof-of-principle metabolite-based test with the ability to predict cancer recurrence based on the ancestry of the patient. In the longer term, this test will be validated and translated into a clinical assay that should have the ability to predict the recurrence of prostate cancer in an ancestry informed fashion in prostate cancer patients.

我们的研究计划的长期目标是减少前列腺癌对 非裔美国人。在此应用中，我们使用代谢组分析的技术来发现 非裔美国人和欧美的前列腺癌之间的潜在生化差异 起源。代谢组学描述了量化代谢物水平（例如，小分子）的科学。 是细胞代谢的副产品。也就是说，在这种分析中，我们正在衡量 由细胞的功能机械产生的生化实体（或代谢产物）。有知识 在特定代谢物的身份中，我们可以推断出产生它们的生物学过程，从而获得 深入了解细胞的新陈代谢。鉴于此，应用的指导原则是独特的生化原则 非裔美国人和欧美血统的前列腺癌之间存在差异， 差异会影响肿瘤及其周围细胞称为基质的细胞，使它们可以一起 促进肿瘤的进展。由于非裔美国人前列腺癌的增长和进展更多 比欧美肿瘤迅速，我们的研究可能会解决一些基本原因 前列腺癌健康差异。此外，它还将构建一个可以预测的首个生物标志物面板 血统中的癌症复发证实了患有前列腺癌的非洲裔美国男性。在这个建议中，我将 确定在非裔美国人前列腺癌中驱动肌苷升高的生化机制， ii）评估肌苷升高在使非洲裔美国肿瘤侵略性并引起肿瘤方面的功能 促进周围基质细胞中的特性和iii）为基于等离子体的代谢标记 非裔美国人的生化复发。在这项研究的结论中，我们将开发 种族衍生的前列腺癌代谢组模型以及确定的未来药物的候选途径 定位。我们还将建立基于原代代谢物的原则证明，并能够预测癌症 基于患者的祖先复发。从长远来看，该测试将得到验证和翻译 进行临床评估，该评估应具有预测血统中前列腺癌复发的能力 前列腺癌患者的知情时尚。

项目成果

Repair-Assisted Damage Detection Reveals Biological Disparities in Prostate Cancer between African Americans and European Americans.

• DOI: 10.3390/cancers14041012
• 发表时间: 2022-02-17
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Krieger KL;Gohlke JH;Lee KJ;Piyarathna DWB;Castro PD;Jones JA;Ittmann MM;Gassman NR;Sreekumar A
• 通讯作者: Sreekumar A