A role of FAM3B in suppressing prostate cancer progression

最近一些新药的开发和FDA的批准预示着前列腺癌的新纪元即将到来 心理治疗。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 前列腺癌将进展为转移性并开发有效的治疗方法来早期治疗以阻止它们 疾病的发展。拟议的研究针对这些关键的需要领域。在我们的初步研究中，通过 对近400个临床样本进行了无偏见的分析，并随后进行了实验验证，我们发现 FAM3B(具有序列相似性的家族3B)基因缺失是肺癌转移进展的潜在驱动因素 前列腺癌。我们进一步发现，FAM3B的缺失会导致氧化磷酸化减弱，并 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FAM3B基因的缺失会导致前列腺癌的进展 晚期，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特定的目标进行检验，这两个目标使用了临床上相关的 模型系统和临床数据集。目标1将剖析FAM3B损耗调制的机制 葡萄糖代谢在推动疾病进展中的作用。AIM 2将确定FAM3B缺失是前列腺癌的驱动因素 癌症进展。 通过从机制和功能的角度询问FAM3B-葡萄糖代谢轴， 拟议的研究将揭示推动前列腺癌进展的新的重要机制，提供新的 标记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 早期有效的治疗。此外，了解FAM3B损失影响的确切机制 葡萄糖代谢和推动疾病进展将有助于未来特定靶向的抑制剂的设计 FAM3B-低位前列腺癌。总体而言，该应用程序解决了与前列腺高度相关的一个区域 癌症领域，从生物学和翻译的角度来看。

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.