A role of FAM3B in suppressing prostate cancer progression

FAM3B 在抑制前列腺癌进展中的作用

• 批准号: 10625388
• 负责人: Yan Dong
• 金额: --
• 依托单位: SOUTHEAST LOUISIANA VETERANS HEALTH CARE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625388
• 关键词: Address; Animal Model; Area; Attenuated; Automobile Driving; Biochemical; Biological; Biological Markers; Biological Models; Biology; Cancer Relapse; Castration; Cell Line; Cells; Chromosomal Insertion; Chromosomal Rearrangement; Clinical; Clinical Data; Data Set; Development; Diagnosis; Disease; Disease Progression; Ectopic Expression; Enzymes; Family; Foundations; Future; Genes; Genetic; Glycolysis; Glycolysis Pathway; Goals; Growth; Health; Healthcare; Human; Knock-out; Knockout Mice; Knowledge; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Modeling; Neoplasm Metastasis; Osteolytic; Oxidative Phosphorylation; Patient-Focused Outcomes; Patients; Prostate; Prostate Cancer therapy; Research; Research Design; Resistance; Role; Sampling; TMPRSS2 gene; Testing; Therapeutic; Therapeutic Trials; Tumor stage; VCaP; Validation; Veterans; aerobic glycolysis; anticancer research; assay development; biomarker driven; clinically relevant; design; diminished oxidative phosphorylation; effective therapy; genetic makeup; glucose metabolism; inhibitor; interstitial; novel; novel marker; novel therapeutics; patient derived xenograft model; patient population; preclinical study; prostate cancer model; prostate cancer progression; subcutaneous; trial design

The recent development and FDA approval of a number of new drugs heralded a new era of prostate cancer therapy. However, metastatic prostate cancer remains a fatal disease. Thus, there is a critical need to identify prostate cancers that will progress to metastatic and develop effective therapies to treat them early to stop disease progression. The proposed study addresses these critical areas of need. In our preliminary studies, via an unbiased analysis of close to 400 clinical samples and subsequent experimental validation, we identified loss of the FAM3B (family with sequence similarity 3B) gene as a potential driver of metastatic progression of prostate cancer. We further found that FAM3B loss leads to diminished oxidative phosphorylation and enhanced aerobic glycolysis, which is a known mechanism of prostate cancer progression. Building on these novel findings, we hypothesize that loss of FAM3B drives prostate cancer progression to an advanced stage and that this is mediated, at least in part, by suppressing oxidative phosphorylation and promoting aerobic glycolysis. This hypothesis will be tested by two specific aims that employ clinically relevant model systems and clinical datasets. Aim 1 will dissect the mechanism by which FAM3B loss modulates glucose metabolism in driving disease progression. Aim 2 will establish FAM3B loss as a driver of prostate cancer progression. By interrogating the FAM3B-glucose-metabolism axis from a mechanistic and functional perspective, the proposed study will reveal a new and important mechanism driving prostate cancer progression, provide a new marker to better identify those patients, including the Veterans, with aggressive disease so that they can be treated early and effectively. Moreover, understanding the precise mechanisms by which FAM3B loss impacts glucose metabolism and drives disease progression will aid in future design of inhibitors that specifically target FAM3B-low prostate cancer. Overall, the application addresses an area that is highly relevant to the prostate cancer field, from both biological and translational perspectives.

近期多项新药的研发和FDA批准预示着前列腺癌新时代的到来 治疗。然而，转移性前列腺癌仍然是一种致命的疾病。因此，迫切需要确定 将进展为转移性的前列腺癌，并开发有效的疗法来及早治疗以阻止它们 疾病进展。拟议的研究解决了这些关键的需求领域。在我们的初步研究中，通过 通过对近 400 个临床样本的公正分析和随后的实验验证，我们发现 FAM3B（序列相似性 3B 家族）基因的缺失是肿瘤转移进展的潜在驱动因素 前列腺癌。我们进一步发现 FAM3B 缺失会导致氧化磷酸化减弱， 有氧糖酵解增强，这是前列腺癌进展的已知机制。 基于这些新发现，我们假设 FAM3B 的缺失会导致前列腺癌进展为 晚期阶段，这至少部分是通过抑制氧化磷酸化和 促进有氧糖酵解。这一假设将通过两个具体目标进行检验，这些目标采用临床相关的方法 模型系统和临床数据集。目标 1 将剖析 FAM3B 损失调节的机制 葡萄糖代谢驱动疾病进展。目标 2 将确立 FAM3B 缺失作为前列腺的驱动因素 癌症进展。 通过从机制和功能角度探讨 FAM3B 葡萄糖代谢轴， 拟议的研究将揭示驱动前列腺癌进展的新的重要机制，提供新的方法 标记物，以更好地识别那些患有侵袭性疾病的患者，包括退伍军人，以便他们能够 及早有效治疗。此外，了解 FAM3B 损失影响的精确机制 葡萄糖代谢并驱动疾病进展将有助于未来设计专门针对的抑制剂 FAM3B-低前列腺癌。总体而言，该应用程序涉及与前列腺高度相关的领域 从生物学和转化的角度来看，癌症领域。