Leveraging polyamine metabolic stress as a novel therapy for prostate cancer

利用多胺代谢应激作为前列腺癌的新疗法

• 批准号: 9229829
• 负责人: HAYLEY AFFRONTI
• 金额: $ 3.06万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-21 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9229829
• 关键词: Adverse effects; Affect; Alternative Therapies; American; Anabolism; Androgens; Apoptosis; Back; Budgets; Cancer Etiology; Carbon; Cell Line; Cells; Clinical; Clinical Trials Design; Combined Modality Therapy; Comorbidity; Comprehensive Cancer Center; Cytostatics; Data Set; Dependence; Development; Diagnosis; Diet; Enzymes; Epithelial Cells; Folic Acid; Foundations; Future; Genes; Genetic; Genetically Engineered Mouse; Goals; Grant; Growth; Imaging Techniques; In Vitro; Incidence; Intervention; Kinetics; LNCaP; Lead; Localized Disease; Malignant Neoplasms; Malignant neoplasm of prostate; Mass Spectrum Analysis; Mentors; Metabolic; Metabolic Pathway; Metabolic stress; Metabolism; Methionine; Methionine Metabolism Pathway; Mono-S; Morbidity - disease rate; Mus; Nucleotides; Nude Mice; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylases; Polyamine Catabolism; Polyamines; Positioning Attribute; Postdoctoral Fellow; Principal Investigator; Process; Prostate; Prostatectomy; Prostatic; Quality of life; Radical Prostatectomy; Radiosurgery; Recurrence; Recycling; Regulation; Reproducibility; Research; Research Personnel; Research Project Grants; Risk; S-Adenosylmethionine; Series; Spermidine/Spermine N1-Acetyltransferase; Stress; System; Technical Expertise; Techniques; Testing; Therapeutic; Tissues; Toxic effect; Translational Research; Up-Regulation; Work; Writing; Xenograft procedure; cancer therapy; career; career development; common treatment; cytotoxic; experience; follow-up; high risk; in vivo; men; metabolomics; mortality; mouse model; novel; novel therapeutics; prevent; skills; standard care; success; symposium

The most common treatment options for prostate cancer (CaP) patients initially presenting with localized disease are surgery and radiation. However, both approaches can result in significant side-effects, which impact quality of life. Furthermore, some patients present with comorbidities that make these approaches unviable options. A low-risk, low-morbidity therapy would provide an important new alternative. My thesis project studies the prospects of using novel treatments as an alternative option for patients presenting with localized CaP by taking advantage of inherent metabolic strain in prostate cells due to their extraordinary level of polyamine biosynthesis. Recent findings have shown that the high levels of polyamine biosynthesis, which consumes S-adenosylmethionine (SAM) pools, puts enormous demands on one-carbon metabolism and the methionine cycle to maintain nucleotide and SAM pools. This state of extraordinary levels of polyamine biosynthesis is enhanced in CaP. The system is driven by the activity of spermidine/spermine N1- acetyltransferase (SSAT), which acetylates the polyamines leading to their secretion into the lumen, requiring cells to synthesize polyamines to maintain intracellular levels. To overcome this stress, the methionine salvage pathway (MSP) recycles the one-carbon unit lost to polyamine biosynthesis back to the methionine cycle, allowing for replenishment of SAM pools. The rate-limiting enzyme involved in this process is methylthioadenosine phosphorylase (MTAP), and our preliminary findings strongly suggest that this pathway is a major player in homeostatic regulation of metabolite pools in CaP cells given their high level of flux through the polyamine biosynthetic pathway. Our central hypothesis is that the MSP is critical to CaP due to high metabolic flux through polyamine biosynthesis, and that this dependence can be enhanced by increasing the activity of SSAT. Therefore, targeting these pathways may provide novel therapeutic strategies to treat localized CaP. Additionally, this approach leverages a prostate specific stress, providing a therapeutic window in which the CaP, and perhaps prostate tissue, can be strongly affected with limited toxicity to other tissues in comparison to standard treatment. This hypothesis has been tested previously in vitro (discussed in Aim 1) with future work underway to test this hypothesis in vivo (discussed in Aim 2). We propose that by combining polyamine catabolism upregulation (to increase metabolic stress) and MSP inhibition (to prevent mitigation of that stress) will lead to crisis and apoptosis in CaP cells. We expect that simultaneous targeting of multiple, converging pathways that are exceptionally important for prostate will provide a new therapeutic option for patients with localized CaP. Our long term goal is to take advantage of this in a clinical setting to provide an alternative therapy for patients with localized CaP. Additionally, this project lays the foundation for pursuing a postdoctoral position (discussed in Aim 3) with a principal investigator well-versed in leveraging metabolic stresses to develop cancer therapies as I strive to become a highly productive independent investigator.

前列腺癌（CAP）患者最常见的治疗选择 疾病是手术和辐射。但是，两种方法都可能导致重大的副作用，这 影响生活质量。此外，一些患者出现了合并症 不可行的选项。低风险的低风险疗法将提供一个重要的新替代方案。我的论文 项目研究使用新型治疗作为出现的患者的替代选择的前景 由于其非凡水平，通过利用前列腺细胞中固有的代谢菌株的局部盖 多胺生物合成。最近的发现表明，高水平的多胺生物合成，这是 消耗S-腺苷甲氨酸（SAM）池，对单碳代谢提出了巨大的需求， 蛋氨酸循环维持核苷酸和SAM池。这种非凡的多胺水平 CAP上的生物合成增强。该系统是由精子/精子N1-的活性驱动的 乙酰基转移酶（SSAT），乙酰化多胺导致其分泌到管腔中，需要 细胞合成多胺以维持细胞内水平。为了克服这种压力，蛋氨酸打捞 途径（MSP）回收损失于多胺生物合成的一碳单元回到蛋氨酸循环， 允许补充山姆池。此过程中涉及的限速酶是 甲基噻可腺苷磷酸化酶（MTAP），我们的初步发现强烈表明该途径是 鉴于其高水平的通量通过 多胺生物合成途径。我们的中心假设是，由于高的MSP对于CAP至关重要 通过多胺生物合成的代谢通量，可以通过增加这种依赖性来增强这种依赖性 SSAT的活动。因此，针对这些途径可能会提供新颖的治疗策略来治疗 局部上限。此外，这种方法利用前列腺特定的压力，提供治疗窗口 其中瓶盖和可能的前列腺组织可能会受到对其他组织毒性有限的强烈影响 与标准处理比较。该假设先前已经在体外进行了检验（在AIM 1中进行了讨论） 随着未来在体内检验这一假设的工作（在AIM 2中进行了讨论）。我们通过结合提出 多胺分解代谢上调（增加代谢应激）和MSP抑制（以防止减轻 这种压力）将导致帽细胞的危机和凋亡。我们希望同时定位多个 对前列腺非常重要的融合途径将为您提供新的治疗选择 局部帽的患者。我们的长期目标是在临床环境中利用这一点，以提供 局部帽患者的替代疗法。此外，该项目为追求 博士后职位（在目标3中讨论）与一位精通代谢的主要研究人员 当我努力成为一名高产的独立研究者时，压力是发展癌症疗法的。