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: 10454772
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454772
• 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; Data Set; Development; Diagnosis; Disease; Disease Progression; ERG gene; 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; Metastatic to; 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; base; 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.

最近开发和FDA批准的一些新药预示着前列腺癌的新时代 疗法然而，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 前列腺癌将发展为转移性，并开发有效的治疗方法来早期治疗它们， 疾病进展。拟议的研究涉及这些关键的需要领域。在初步研究中，通过 通过对近400份临床样本的无偏分析和随后的实验验证，我们发现 FAM 3B（具有序列相似性3B的家族）基因的缺失作为转移性进展的潜在驱动因素， 前列腺癌我们进一步发现，FAM 3B缺失导致氧化磷酸化减少， 增强有氧糖酵解，这是前列腺癌进展的已知机制。 基于这些新的发现，我们假设FAM 3B的缺失驱动前列腺癌进展到晚期。 晚期，这至少部分是通过抑制氧化磷酸化介导的， 促进有氧糖酵解。这一假设将通过两个特定的目标进行检验， 模型系统和临床数据集。目的1将剖析FAM 3B损失调节 葡萄糖代谢促进疾病进展。目标2将确立FAM 3B缺失作为前列腺增生的驱动因素。 癌症进展 通过从机制和功能的角度询问FAM 3B-葡萄糖代谢轴， 拟议的研究将揭示一种新的重要机制，推动前列腺癌的进展，提供一个新的 标记，以更好地识别这些患者，包括退伍军人，与侵略性疾病，使他们可以 早期有效治疗。此外，了解FAM 3B损失影响的确切机制， 葡萄糖代谢和驱动疾病进展将有助于未来设计特异性靶向 FAM 3B-低前列腺癌。总的来说，该应用程序解决了一个与前列腺高度相关的领域 癌症领域，从生物学和翻译的角度。