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. .

摘要 患有需要治疗的局部疾病的前列腺癌（CaP）患者的标准治疗是手术或 辐射局部复发或转移性CaP患者依赖雄激素剥夺治疗（ADT）。虽然 患者最初对ADT有反应，大多数患者将通过各种机制对治疗产生耐药性， 重新激活雄激素信号。该领域的研究指出，表观遗传可塑性的增加， CaP是耐药性的贡献者，这导致了对靶向CaP的几种表观遗传疗法的研究。 虽然表观遗传疗法已经成功地用于治疗血液恶性肿瘤，但它们在治疗血液恶性肿瘤方面的成功仍然存在。 实体瘤仅限于临床前研究。它们作为单一药剂的使用由于全身性 毒性，因为这些药物针对所有细胞类型中使用的基本表观遗传酶。联合治疗， 需要改进靶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CaP细胞中基于其高水平多胺（PA）的固有代谢应变， 生物合成通过PA途径的异常水平的通量是由亚精胺/精胺N1驱动的。 乙酰转移酶（SSAT），其利用乙酰辅酶A使PA乙酰化并导致其分泌到细胞中。 前列腺腔这导致一个碳代谢，以提供S-腺苷甲硫氨酸（SAM）库，其是 在PA生物合成中消耗以补充细胞内PA。我们目前的治疗策略 通过增加SSAT活性结合抑制甲硫氨酸补救途径， 合成时损失的单位来补充SAM最近的研究结果表明，这种代谢中断影响SAM 和乙酰辅酶A体内平衡。我们的中心假设是，通过PA代谢诱导通量， 连接的一碳代谢破坏SAM和乙酰辅酶A池的稳态，使CaP更多 对靶向SAM和乙酰辅酶A利用的表观遗传疗法敏感。因此，通过了解 表观遗传后果和适应性反应强调SAM和乙酰辅酶A稳态，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，降低全身毒性。的 将通过追求两个具体目标来测试假设：1）确定前列腺癌细胞如何适应 破坏甲基和乙酰库的体内平衡。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这是否或如何传播到表观基因组。我们提出 将增加多胺催化剂和MSP抑制的代谢干预与干扰 组蛋白甲基转移酶或乙酰转移酶活性。我们希望代谢疗法的结合 利用靶向SAM和乙酰辅酶A的表观遗传疗法来抑制SAM和乙酰辅酶A的使用，将导致提高SAM和乙酰辅酶A的功效。 表观遗传疗法和降低的全身毒性。 .