Targeting the Metabolome in Androgen Receptor-driven Castration-resistant Prostate Cancer

新陈代谢的改变，特别是脂肪生成的改变是前列腺癌进展和 从良性到恶性的前列腺上皮涉及从线粒体氧化代谢到 为癌细胞中的有氧糖酵解产生细胞过程所需的能量。此过程对以下各项至关重要 细胞增殖和新细胞膜的合成，包括雄激素驱动的持续增殖 大多数去势抵抗前列腺癌(CRPC)中的受体。驱动这些代谢变化的机制 目前还不完全清楚，但脂肪酸合成酶内源性增加内源性脂肪生成 雄激素受体驱动的基因(FASN)和5‘AMP激活的激酶(AMPK)活性降低是 驱动CRPC的代谢过程改变的关键成分。在我们的初步数据中，我们证明了 两种新药将改变这两个基因的功能，抑制FASN和激活AMPK 在体内外抑制去势耐药肿瘤的生长。我们已经证明了这种改变 在新陈代谢中会抑制由AR结构性活性变异体驱动的肿瘤生长 我目前的退伍军人荣誉奖。这个项目的假设是AMPK的靶向激活 通过调节脂肪生成进而抑制AR表达和 活动。为了解决这一假设，我们将首先演示AMPK、AMPK相关的表达 组织芯片(TMA)中的亚基(如磷酸丝氨酸486、对乙酰辅酶A羧基酶)和FASN 原发前列腺癌、转移性CRPC肿瘤和前列腺癌患者衍生(PDX)模型，以及 确定与AR、AR-V7和AR变种的相关性。我们之前已经显示出很强的相关性 转移性前列腺癌CRPC中FASN表达与AR的关系此外，其他研究也有 显示激活的AMPK水平在前列腺癌和转移性前列腺癌的进展中降低 原发性前列腺癌，这可能预示着转移性疾病的发展。因此，我们将研究如何使用 华盛顿大学/弗雷德·哈奇森前列腺癌计划提供了大量的患者材料，以 确定这些癌症进展因子的临床表达。接下来，我们将通过以下方式确定该机制 该AMPK被BKI 1553激活并影响AR转录输出。我们的初步数据显示 通过Ser486去磷酸化激活AMPK抑制AR驱动的CRPC的生长。此外，这一点 活性被BKI 1553激活，但仅在AR阳性的PCa细胞中激活。在这个目标中，我们将确定 MOA对BKI1553激活AMPK的潜在靶点(S)及其随后抑制AR的机制 表达和转录活性。接下来我们将评估BKI 1553的抗增殖作用是否包括 单不饱和脂肪酸(MUSFAs)酶的转录和转录后调控 新陈代谢。最后，体内实验证实了AMPK的激活和FASN对CRPC的抑制作用。我们会 扩展到AIM 1中确定的FASN和/或AMPK表达发生变化的PCA PDX模型 为了更好地说明BKI 1553和IP1991对一系列CRPC的适用性。

Alterations in metabolism especially lipogenesis are unique to prostate cancer progression and the changes from benign to malignant prostate epithelium involves a switch from mitochondrial oxidative metabolism to generate energy needs for cellular processes to aerobic glycolysis in cancer cells. This process is critical for cell proliferation and new cell membrane synthesis including the continued proliferation driven by the androgen receptor in most castration resistant prostate cancers (CRPC). Mechanisms driving these metabolic alterations are not fully understood but the endogenous increase in endogenous lipogenesis by fatty acid synthase (FASN), an androgen receptor driven gene, and a decrease in 5’AMP-activated kinase (AMPK) activity are crucial components of the altered metabolic processes driving CRPC. In our Preliminary Data we demonstrate that alteration in function of these two genes, inhibition of FASN and activation of AMPK, by two new drugs will suppress growth of enzalutamide castrate resistant tumors in vitro and in vivo. We have shown that alteration in metabolism will suppress the growth of tumors driven by AR constitutively active variants that were the basis of my current VA Merit Review. The hypothesis of this project is that targeting activation of AMPK suppresses PCa proliferation by regulating lipogenesis with subsequent inhibition of AR expression and activity. In order to address this hypothesis we will first demonstrate expression of AMPK, AMPK-related subunits (e.g., phospho serine 486, p-acetyl coenzyme A carboxylase), and FASN in tissue microarrays (TMA) of primary prostate cancer, metastatic CRPC tumors, and prostate cancer patient-derived (PDX) models, and determine correlation with AR, AR-V7, and AR-variants. We have previously shown a strong correlation between FASN expression and AR in CRPC in metastatic prostate cancer. In addition, other studies have shown activated AMPK levels decrease in progression from primary to metastatic prostate cancer and for primary PCa, this may be predictive of development of metastatic disease. Therefore, we will examine use the extensive patient material available in the University of Washington/Fred Hutchison prostate cancer program to determine clinical expression of these cancer progression factors. Next we will determine the mechanism by which AMPK is activated by BKI 1553 and affects AR transcriptional output. Our preliminary data indicates that activation of AMPK by the dephosphorylation of Ser486 suppresses growth of AR-driven CRPC. Further, this activity is activated by BKI 1553 but only in PCa cells that are AR positive. In this aim we will determine the MOA of BKI 1553 activation of AMPK, potential target(s) and its subsequent mechanism of suppression of AR expression and transcriptional activity. Next we will assess if antiproliferative actions of BKI 1553 include transcriptional and post-transcriptional regulation of enzymes in monounsaturated fatty acids (MUSFAs) metabolism. Finally, demonstrate in vivo activity of AMPK activation and FASN inhibition on CRPC. We will expand to PCa PDX models identified in Aim 1 where FASN and/or AMPK expression has changed in progression to CRPC in order to better show the applicability of BKI 1553 and IP1991 to a range of CRPCs.