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

靶向雄激素受体驱动的去势抵抗性前列腺癌的代谢组

• 批准号: 10015557
• 负责人: Stephen R. Plymate
• 金额: --
• 依托单位: VA PUGET SOUND HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10015557
• 关键词: 5' -AMP-activated protein kinase; Acetyl-CoA Carboxylase; Addendum; Address; Adenosine Monophosphate; Affect; Androgen Antagonists; Androgen Receptor; Androgen Suppression; Automobile Driving; Benign; Cancer Patient; Cell Proliferation; Cell Respiration; Cell membrane; Cell physiology; Cells; Clinical; Data; Development; Diagnosis; Disease; Disease Progression; Enzymes; Epithelial; Epithelium; Fatty-acid synthase; Genes; Genetic; Genetic Transcription; Growth; Immunotherapy; In Vitro; Length; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Metabolic; Metabolism; Metastatic Prostate Cancer; Metastatic to; Mitochondria; Modeling; Monounsaturated Fatty Acids; Output; Pathway interactions; Patients; Population; Post-Transcriptional Regulation; Process; Progress Reports; Prostate; Prostatic Neoplasms; Protein Dephosphorylation; Protein Isoforms; Protein Kinase; Publishing; Receptor Signaling; Recurrent disease; Recurrent tumor; Resistance; Role; Serine; Signal Pathway; Solid Neoplasm; Therapeutic; Tissue Microarray; Transcriptional Regulation; Universities; Variant; Veterans; Washington; Work; abiraterone; aerobic glycolysis; androgen deprivation therapy; cancer cell; castration resistant prostate cancer; clinical development; constitutive active receptor; improved; in vivo; inhibitor/antagonist; lipid biosynthesis; lipid metabolism; membrane synthesis; men; metabolome; new therapeutic target; novel drug class; novel therapeutics; optimal treatments; precision oncology; programs; prostate cancer cell; prostate cancer progression; receptor expression; targeted agent; targeted treatment; therapy development; therapy resistant; tumor; tumor growth; tumor metabolism; tumor progression

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.

新陈代谢的改变，尤其是脂肪生成的改变，是前列腺癌进展所特有的，并且这些改变 从良性到恶性前列腺上皮涉及从线粒体氧化代谢到 产生细胞过程中的有氧糖酵解所需的能量，这个过程对于癌细胞来说至关重要。 细胞增殖和新细胞膜合成，包括雄激素驱动的持续增殖 大多数去势抵抗性前列腺癌 (CRPC) 中的受体驱动这些代谢改变。 尚未完全了解，但脂肪酸合酶导致内源性脂肪生成的内源性增加 (FASN)，一种雄激素受体驱动基因，以及 5'AMP 激活激酶 (AMPK) 活性的降低 在我们的初步数据中，我们证明了驱动 CRPC 的代谢过程改变的关键组成部分。 两种新药将改变这两个基因的功能，即抑制 FASN 和激活 AMPK 我们已经在体外和体内证明了这种改变。 代谢中的活性成分将抑制由 AR 组成型活性变体驱动的肿瘤生长，这些变体是 AR 的基础 我目前的 VA 绩效评估 该项目的假设是针对 AMPK 的激活。 通过调节脂肪生成并随后抑制 AR 表达来抑制 PCa 增殖 为了解决这个假设，我们将首先证明 AMPK 的表达，AMPK 相关。 组织微阵列 (TMA) 中的亚基（例如磷酸丝氨酸 486、p-乙酰辅酶 A 羧化酶）和 FASN 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 我们之前已经显示出很强的相关性。 此外，其他研究还发现转移性前列腺癌 CRPC 中 FASN 表达与 AR 之间的关系。 研究显示，从原发性前列腺癌到转移性前列腺癌的进展过程中，激活的 AMPK 水平会降低，并且 原发性 PCa，这可能预示着转移性疾病的发展，因此，我们将使用该方法进行检查。 华盛顿大学/Fred Hutchison 前列腺癌项目提供了大量患者材料 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其机制。 AMPK 被 BKI 1553 激活并影响 AR 转录输出。 通过 Ser486 去磷酸化激活 AMPK 可以抑制 AR 驱动的 CRPC 的生长。 BKI 1553 激活该活性，但仅在 AR 阳性的 PCa 细胞中激活。 BKI 1553 激活 AMPK 的 MOA、潜在靶点及其随后抑制 AR 的机制 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 (MUSFA) 中酶的转录和转录后调控 最后，我们将证明 AMPK 激活和 FASN 对 CRPC 的抑制作用的体内活性。 扩展到目标 1 中确定的 PCa PDX 模型，其中 FASN 和/或 AMPK 表达已发生变化 为了更好地展示 BKI 1553 和 IP1991 对一系列 CRPC 的适用性，我们进行了 CRPC 的进展。