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

代谢的改变尤其是脂肪生成是前列腺癌进展所特有的， 从良性前列腺上皮到恶性前列腺上皮的转变涉及从线粒体氧化代谢到 产生癌细胞有氧糖酵解细胞过程所需的能量。这一过程对于 细胞增殖和新细胞膜合成，包括雄激素驱动的持续增殖 受体在大多数去势抵抗性前列腺癌（CRPC）。驱动这些代谢改变的机制 但通过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（FXR）和5 'AMP激活的激酶（AMPK）活性的降低， 改变的代谢过程的重要组成部分驱动CRPC。在我们的初步数据中，我们证明 这两种基因功能的改变，即两种新药对FXR的抑制和AMPK的激活， 在体外和体内抑制恩杂鲁胺去势抗性肿瘤生长。我们已经证明， 将抑制由AR组成型活性变体驱动的肿瘤生长， 退伍军人事务部的优秀评估本项目的假设是，靶向激活AMPK， 通过调节脂肪生成并随后抑制AR表达来抑制PCa增殖， 活动为了解决这一假设，我们将首先证明AMPK的表达，AMPK相关的 子单元（例如，磷酸丝氨酸486，p-乙酰辅酶A羧化酶），和组织微阵列（TMA）中的叶酸 原发性前列腺癌、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变体的相关性。我们之前已经证明了 在转移性前列腺癌CRPC中FXR表达和AR之间的关系。此外，其他研究也 显示从原发性前列腺癌到转移性前列腺癌的进展中激活的AMPK水平降低， 对于原发性PCa，这可以预测转移性疾病的发展。因此，我们将研究如何使用 华盛顿大学/Fred Hutchison前列腺癌项目提供了大量患者资料， 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Ser 486的去磷酸化激活AMPK抑制AR驱动的CRPC的生长。此外，这 活性被BKI 1553激活，但仅在AR阳性的PCa细胞中。为此，我们将确定 BKI 1553激活AMPK的MOA、潜在靶点及其抑制AR的后续机制 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 单不饱和脂肪酸中酶的转录和转录后调节（MUSFAs） 新陈代谢.最后，证明AMPK激活和FcB抑制对CRPC的体内活性。我们将 扩展到目标1中确定的PCa PDX模型，其中FXR和/或AMPK表达在目标1中发生变化。 为了更好地显示BKI 1553和IP 1991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.