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

摘要 患有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。局部复发或转移性 CaP 患者依赖雄激素剥夺疗法 (ADT)。虽然 患者最初对 ADT 有反应，大多数人会通过各种机制对治疗产生耐药性 重新激活雄激素信号传导。该领域的研究表明，表观遗传可塑性的增加是一种 导致耐药性的因素，这导致了针对 CaP 的几种表观遗传疗法的研究。 虽然表观遗传疗法在治疗血液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。由于系统性的原因，它们作为单一药物的使用受到限制 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。联合疗法 需要提高靶标特异性以减少表观遗传疗法的全身毒性。我们的建议旨在 利用 CaP 细胞中基于高水平多胺 (PA) 的固有代谢菌株 生物合成。通过 PA 途径的非凡通量是由亚精胺/精胺 N1- 驱动的 乙酰转移酶 (SSAT)，利用乙酰辅酶 A 乙酰化 PA，并导致其分泌到 前列腺腔。这使一种碳代谢产生 S-腺苷甲硫氨酸 (SAM) 库，这些库是 PA 生物合成中消耗以补充细胞内 PA。我们目前的治疗策略会增加压力 通过增加 SSAT 活性并抑制蛋氨酸回收途径，从而回收碳 失去合成以补充 SAM 的单位。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稳态。我们的中心假设是通过 PA 代谢诱导通量 连接一碳代谢破坏 SAM 和乙酰辅酶 A 池稳态，使 CaP 更 对针对 SAM 和乙酰辅酶 A 利用的表观遗传治疗敏感。因此，通过了解 表观遗传后果和对应激 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，同时降低全身毒性。的 该假设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 甲基和乙酰基池稳态的破坏。 2) 确定应激 PA 代谢如何改变 CaP 对表观遗传治疗的敏感性以及其是否或如何传播到表观基因组。我们建议 将增加多胺分解代谢和 MSP 抑制的代谢干预措施与干扰相结合 组蛋白甲基转移酶或乙酰转移酶活性。我们预计代谢疗法的组合 通过针对 SAM 和乙酰辅酶 A 的使用的表观遗传疗法来强化 SAM 和乙酰辅酶A，将提高 表观遗传治疗并降低全身毒性。 。

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. .