Leveraging polyamine metabolic stress to enhance sensitivity to epigenetic therapy for Prostate Cancer

利用多胺代谢应激提高前列腺癌表观遗传治疗的敏感性

• 批准号: 10215234
• 负责人: ARYN ROWSAM
• 金额: $ 3.15万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10215234
• 关键词: Acetyl Coenzyme A; Address; Affect; Aftercare; American; Anabolism; Androgens; Back; Cancer Etiology; Cancer Patient; Carbon; Caring; Castration; Cell Death; Cell Line; Cells; Cessation of life; Chromatin; Combined Modality Therapy; Consumption; Data; Disease; Dose; Drug Targeting; Enzymes; Epigenetic Process; Epithelial Cells; Foundations; Genes; Genome; Genomics; Goals; Hematologic Neoplasms; Homeostasis; Hormones; Human; In Vitro; Individual; Intervention; Investigation; LNCaP; Libraries; Localized Disease; Malignant neoplasm of prostate; Measures; Metabolic; Metabolic stress; Metabolism; Methionine; Methyltransferase; Operative Surgical Procedures; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phosphorylases; Polyamine Catabolism; Polyamines; Positioning Attribute; Prostate; Prostate Cancer therapy; Prostatic; Radiation; Reading; Recurrence; Recycling; Refractory Disease; Regulation; Research; Resistance; Resources; S-Adenosylmethionine; Signal Transduction; Solid Neoplasm; Specificity; Spermidine; Spermidine/Spermine N1-Acetyltransferase; Spermine; Stress; Testing; Therapeutic; Time; Tissues; Toxic effect; Transferase; Treatment Efficacy; Xenograft procedure; androgen deprivation therapy; androgen sensitive; base; biological adaptation to stress; cancer diagnosis; castration resistant prostate cancer; cell type; clinically relevant; epigenetic drug; epigenetic regulation; epigenetic therapy; epigenome; histone acetyltransferase; histone methyltransferase; histone modification; improved; in vivo; in vivo Model; insight; men; metabolomics; novel; preclinical study; prostate cancer cell; response; small hairpin RNA; standard of care; success; systemic toxicity; targeted treatment; therapy resistant; treatment response

Abstract The standard of care for prostate cancer (CaP) patients with localized disease requiring treatment is surgery or radiation. Those with local recurrence or metastatic CaP rely on androgen deprivation therapy (ADT). Although patients initially respond to ADT, most will become resistant to therapy through various mechanisms to reactivate androgen signaling. Research in the field has pointed to increased epigenetic plasticity as a contributor to resistance, which has resulted in the investigation of several epigenetic therapies targeting CaP. While epigenetic therapies have been successful for treatment of hematological malignancies, their success in solid tumors has been limited to preclinical studies. Their use as single agents are limited due to systemic toxicities, as the drugs target basic epigenetic enzymes used in all cell types. Combination therapies to improve target specificity are needed to reduce systemic toxicity of epigenetic therapies. Our proposal aims to take advantage of an inherent metabolic strain in CaP cells based on their high level of polyamine (PA) biosynthesis. The extraordinary level of flux through the PA pathway is driven by spermidine/spermine N1- acetyltransferase (SSAT), which utilizes acetyl-CoA to acetylate the PAs and leads to their secretion into the prostatic lumen. This strains one carbon metabolism to provide S-Adenosylmethionine (SAM) pools, which are consumed in PA biosynthesis to replenish intracellular PAs. Our current therapeutic strategy enhances stress by increasing SSAT activity combined with inhibition of the methionine salvage pathway, which recycles carbon units lost to synthesis to replenish SAM. Recent findings indicate that this metabolic disruption affects SAM and acetyl-CoA homeostasis. Our central hypothesis is that induced flux through PA metabolism and connected one carbon metabolism disrupts SAM and acetyl-CoA pool homeostasis, making CaP more sensitive to epigenetic therapy targeting SAM and acetyl-CoA utilization. Therefore, by understanding the epigenetic consequences and adaptive responses to stressed SAM and acetyl-CoA homeostasis, we can leverage this to make epigenetic therapies more efficacious at lower doses, with reduced systemic toxicity. The hypothesis will be tested by pursuing two specific aims: 1) Determine how prostate cancer cells adapt to disruption of methyl and acetyl pool homeostasis. 2) Determine how stressed PA metabolism alters the sensitivity of CaP to epigenetic therapy and whether or how this is propagated to the epigenome. We propose to combine metabolic interventions of increased polyamine catabolism and MSP inhibition with interference of histone methyltransferase or acetyltransferase activity. We expect that combination of metabolic therapies straining SAM and acetyl-CoA with epigenetic therapies targeting their usage will result in increased efficacy of epigenetic therapy and reduced systemic toxicity. .

抽象的 需要治疗的局部疾病的前列腺癌（CAP）患者的护理标准是手术或 辐射。那些具有局部复发或转移性帽的人依赖于雄激素剥夺疗法（ADT）。虽然 患者最初对ADT做出反应，大多数将通过各种机制对治疗具有抵抗力 重新激活雄激素信号。该领域的研究指出，表观可塑性增加了 抗药性的贡献者，这导致对靶向帽的几种表观遗传疗法进行了研究。 尽管表观遗传疗法已经成功地治疗了血液学恶性肿瘤，但它们在 实体瘤仅限于临床前研究。由于系统性，它们作为单个代理的使用受到限制 毒性，作为所有细胞类型中使用的碱性表观遗传酶的靶向。组合疗法 需要提高目标特异性以降低表观遗传疗法的全身毒性。我们的建议旨在 利用盖细胞中固有的代谢菌株，基于其高水平的多胺（PA） 生物合成。通过PA途径的非凡通量由精子/精子N1-驱动 乙酰基转移酶（SSAT），它利用乙酰辅酶A进行乙酰化PA，并导致其分泌到 前列腺腔。这会使一种碳代谢构成提供S-腺苷甲硫代氨酸（SAM）池，这是 在PA生物合成中消耗以补充细胞内PA。我们当前的治疗策略会增强压力 通过增加SSAT活性结合抑制蛋氨酸拯救途径，该途径回收碳 单位因合成而失去了补充Sam。最近的发现表明，这种代谢破坏会影响SAM 和乙酰-COA稳态。我们的中心假设是通过PA代谢引起的通量和 连接的一种碳代谢破坏了SAM和乙酰-COA池体内平衡，使帽子更多 对靶向SAM和乙酰-COA利用率的表观遗传疗法敏感。因此，通过了解 表观遗传学后果和对压力的SAM和乙酰辅酶A稳态的适应性反应，我们可以 利用这一点使表观遗传疗法在较低剂量下更有效，系统性毒性降低。这 假设将通过追求两个具体目的来检验：1）确定前列腺癌细胞如何适应 甲基和乙酰池稳态的破坏。 2）确定压力PA代谢如何改变 CAP对表观遗传疗法的敏感性以及是否或如何传播表观遗传组。我们建议 结合增加多胺分解代谢和MSP抑制的代谢干预措施与干扰 组蛋白甲基转移酶或乙酰转移酶活性。我们期望代谢疗法的组合 用靶向其使用的表观遗传疗法过滤SAM和乙酰辅酶A将导致提高的功效 表观遗传疗法和降低全身毒性。 。