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

基本信息

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
项目类别：
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

项目摘要

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.

最初出现局部症状的前列腺癌 (CaP) 患者最常见的治疗方案疾病有手术和放射。然而，这两种方法都会导致显着的副作用，影响生活质量。此外，一些患者存在合并症，使得这些方法无法实施不可行的选择。低风险、低发病率的治疗将提供一种重要的新替代方案。我的论文该项目研究了使用新疗法作为患有以下疾病的患者的替代选择的前景利用前列腺细胞中异常水平的固有代谢应变来定位 CaP 多胺生物合成。最近的研究结果表明，高水平的多胺生物合成，消耗S-腺苷甲硫氨酸（SAM）池，对一碳代谢和蛋氨酸循环以维持核苷酸和 SAM 池。这种多胺水平异常高的状态 CaP 的生物合成得到增强。该系统由亚精胺/精胺 N1- 的活性驱动乙酰转移酶（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，蛋氨酸抢救途径（MSP）将多胺生物合成中损失的一碳单元回收回蛋氨酸循环，允许补充 SAM 池。该过程中涉及的限速酶是甲硫腺苷磷酸化酶（MTAP），我们的初步研究结果强烈表明该途径是鉴于 CaP 细胞代谢物库的高水平通量，它是 CaP 细胞代谢物库稳态调节的主要参与者多胺生物合成途径。我们的中心假设是，由于高 MSP 对 CaP 至关重要通过多胺生物合成的代谢通量，并且这种依赖性可以通过增加 SSAT 活动。因此，针对这些途径可能会提供新的治疗策略来治疗局部化的 Cap。此外，这种方法利用前列腺特异性压力，提供治疗窗口其中，CaP（可能还有前列腺组织）可能会受到强烈影响，而对其他组织的毒性有限与标准治疗的比较。该假设之前已在体外进行过测试（目标 1 中讨论）未来的工作正在进行中，以在体内检验这一假设（目标 2 中讨论）。我们建议通过结合多胺分解代谢上调（以增加代谢应激）和 MSP 抑制（以防止缓解这种压力）将导致 CaP 细胞危机和凋亡。我们期望同时瞄准多个，对前列腺异常重要的汇聚途径将为前列腺癌提供新的治疗选择局部 CaP 患者。我们的长期目标是在临床环境中利用这一点来提供局部 CaP 患者的替代疗法。此外，该项目为追求博士后职位（目标 3 中讨论），首席研究员精通利用代谢当我努力成为一名高产的独立研究者时，我强调开发癌症疗法。