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.

许多新药的最新发展和FDA批准预示了前列腺癌的新时代 治疗。但是，前列腺癌仍然是致命的疾病。因此，肯定需要识别 前列腺癌将发展为转移和开发有效的疗法以尽早治疗它们以停止 疾病进展。拟议的研究解决了这些关键需求领域。在我们的初步研究中 对接近400个临床样本和随后的实验验证的无偏分析，我们确定了 FAM3B（具有序列相似性3B）基因的丢失是转移性进展的潜在驱动力 前列腺癌。我们进一步发现，FAM3B损失导致氧化磷酸化降低和 增强的有氧糖酵解，这是前列腺癌进展的已知机制。 在这些新颖的发现的基础上，我们假设FAM3B的损失驱动了前列腺癌的发展 晚期，至少部分通过抑制氧化磷酸化和 促进有氧糖酵解。该假设将通过使用临床相关的两个特定目标来检验 模型系统和临床数据集。 AIM 1将剖析FAM3B损失调制的机制 葡萄糖代谢在推动疾病进展中。 AIM 2将建立FAM3B损失作为前列腺的驱动力 癌症进展。 通过从机械和功能的角度询问FAM3B-葡萄糖 - 代谢轴 拟议的研究将揭示一种驱动前列腺癌进展的新的重要机制，并提供了新的 标记以更好地识别患有侵略性疾病的那些患者，包括退伍军人，以便他们可以 早点有效地治疗。此外，了解FAM3B损失影响的确切机制 葡萄糖代谢并驱动疾病进展将有助于将来设计抑制剂，这些抑制剂特别针对 FAM3B-LOW前列腺癌。总体而言，该应用程序解决了与前列腺高度相关的区域 从生物学和转化的角度来看，癌症领域。