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: 10066630
• 负责人: ARYN ROWSAM
• 金额: $ 3.1万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10066630
• 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 前列腺癌(CAP)患者局部疾病需要治疗的标准是手术或 辐射。那些局部复发或转移的患者依赖于雄激素剥夺治疗(ADT)。虽然 患者最初对ADT有反应，大多数会通过各种机制对治疗产生抵抗力 重新激活雄激素信号。该领域的研究表明，表观遗传可塑性增加是一种 耐药性的因素，这导致了几种针对CAP的表观遗传疗法的调查。 虽然表观遗传疗法在治疗血液系统恶性肿瘤方面取得了成功，但它们在 实体瘤仅限于临床前研究。它们作为单一药物的使用由于系统性的原因而受到限制 毒性，因为这些药物针对的是在所有细胞类型中使用的基本表观遗传酶。综合疗法治疗 为了减少表观遗传疗法的全身毒性，需要提高靶点特异性。我们的建议旨在 利用CAP细胞的高水平多胺(PA)所固有的代谢菌株 生物合成。通过PA途径的超常水平的通量是由亚精胺/精胺N1- 乙酰转移酶(SSAT)，它利用乙酰辅酶A来乙酰化Pas，并导致它们分泌到 前列腺腔。这种菌株的碳代谢提供S-腺苷蛋氨酸(SAM)池，这些池是 消耗在PA的生物合成中，以补充细胞内的PA。我们目前的治疗策略增强了压力 通过增加SSAT活性，同时抑制蛋氨酸回收途径，回收碳 单位失去了合成，以补充SAM。最近的研究结果表明，这种代谢紊乱会影响SAM 和乙酰辅酶A动态平衡。我们的中心假设是通过PA新陈代谢和 Connected One碳代谢扰乱SAM和乙酰-CoA池的动态平衡，使CAP 对以SAM和乙酰辅酶A利用为靶点的表观遗传疗法敏感。因此，通过理解 应激SAM和乙酰辅酶A动态平衡的表观遗传后果和适应性反应，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，并减少全身毒性。这个 假说将通过追求两个具体目标来检验：1)确定前列腺癌细胞如何适应 破坏甲基和乙酰池的动态平衡。2)确定应激状态下的PA代谢如何改变 CAP对表观遗传疗法的敏感性，以及这种敏感性是否或如何传播到表观基因组。我们建议 增加多胺分解代谢和抑制MSP的代谢干预与干预 组蛋白甲基转移酶或乙酰基转移酶活性。我们预计新陈代谢疗法的组合 用针对其使用的表观遗传疗法来筛选SAM和乙酰辅酶A将导致提高 表观遗传疗法，减少全身毒性。 。