Phosphocholine modulation by oncognenic signaling - MRS studies of mechanism

致癌信号传导的磷酸胆碱调节 - MRS 机制研究

• 批准号: 7524300
• 负责人: Sabrina Miriam Ronen
• 金额: $ 32.06万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-03 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7524300
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affect; Animals; Biological Markers; Biometry; Cell Extracts; Cells; Choline; Clinical Trials; Collaborations; Congenital Abnormality; Data; Development; Disease regression; Drug Delivery Systems; Electronics; Enzymes; Equipment; Fatty Acids; Fatty-acid synthase; Goals; Head; Heat-Shock Proteins 90; Image; Investigation; Kinetics; Label; Lead; Life; Link; Lipids; Localized; Magnetic Resonance; Magnetic Resonance Spectroscopy; Maximum Tolerated Dose; Metabolic; Metabolic Pathway; Metabolism; Methodology; Methods; Mitogen Activated Protein Kinase 1; Mitogen-Activated Protein Kinases; Modeling; Molecular; Monitor; Mutation; Oncogenic; Pathway interactions; Patient Care; Patients; Pharmaceutical Preparations; Phosphorylcholine; Physics; Public Health; Reporting; Research; Research Infrastructure; Signal Pathway; Signal Transduction; Site; Time; Toxic effect; Translating; Work; base; cancer therapy; drug development; experience; fatty acid metabolism; glucose metabolism; improved; in vivo; neoplastic cell; novel; pre-clinical research; response; subcutaneous; therapeutic target; tumor; tumor xenograft; tumorigenesis

DESCRIPTION (provided by applicant): Novel anti-cancer therapies increasingly involve targeting of the molecular-genetic abnormalities that result in oncogenesis. However, response to such therapies is often associated with tumor stasis, rather than shrinkage, limiting the utility of conventional imaging methods to monitor early response. Our long-term goal is to develop noninvasive, localized, magnetic resonance (MR)-based methods that detect molecular response to targeted treatments. We have shown that inhibition of signaling via the mitogen activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways results in modulation of MR spectroscopy (MRS)-detectable choline-containing metabolites and in particular phosphocholine (PC). However, our data show that, depending on treatment, inhibition can result either in an increase or in a decrease in PC, limiting its use as a robust biomarker of response. The goal of this application is therefore to determine the mechanisms by which signaling pathways affect cellular metabolism resulting in modulation of PC and other choline-containing metabolites. A secondary goal is to identify and validate biomarkers of response to previously unexplored targeted therapies. This pre-clinical research will result in a better understanding of the mechanisms that lead to changes in choline-containing metabolites. As a result, it will be possible to use the modulation in these metabolites in a more reliable, robust and predictable way to assess response to therapies that target signaling. MAPK and PI3K signaling can affect choline-containing metabolites either directly, by affecting the enzymes involved in choline metabolism, or indirectly, by affecting fatty acid synthase (FASN), which controls fatty acid (FA) synthesis. Thus, we propose to investigate both choline metabolism and fatty acid synthesis. We will combine 1H, 31P and 13C MRS and monitor how modulation of signaling affects the two metabolic pathways, and, consequently, choline-containing metabolites. Specific Aim 1. To determine the effect of fatty acid synthesis on choline metabolism. We will first determine how inhibition of FASN affects FA and choline metabolism. We will study live cells and extracts, and use 1H, 31P, 13C MRS to monitor metabolism. Specific Aim 2. To determine the mechanistic link between signaling pathways and metabolism. Using the same methods as above us will monitor the effect on FA and choline metabolism of 1) MAPK inhibition 2) PI3K inhibition and 3) inhibition of multiple signaling pathways via HSP90. Specific Aim 3. To confirm that the mechanistic findings in cells translate to tumors in vivo. Subcutaneous tumor xenografts will be investigated by 1H, 31P, 13C MRS to confirm that the findings made in Specific Aim 2 hold true in vivo. PUBLIC HEALTH RELEVANCE Magnetic resonance spectroscopy can be used to noninvasively monitor response to novel cancer therapies that target specific oncogenic mutations. However, the exact mechanism behind the magnetic resonance-detectable metabolic changes previously reported following treatment is not clear. In this application we will investigate this link, and our research will result in more robust, reliable, and predictable, noninvasive, magnetic resonance-based indicators of tumor response to treatment, ultimately improving patient care.

描述（由申请人提供）：新型抗癌疗法越来越多地涉及针对导致肿瘤发生的分子遗传异常。然而，对此类疗法的反应通常与肿瘤停滞相关，而不是缩小，这限制了传统成像方法监测早期反应的效用。我们的长期目标是开发基于磁共振 (MR) 的非侵入性局部方法来检测对靶向治疗的分子反应。我们已经证明，通过丝裂原激活蛋白激酶 (MAPK) 和磷脂酰肌醇 3-激酶 (PI3K) 途径抑制信号传导会导致 MR 波谱 (MRS) 可检测的含胆碱代谢物，特别是磷酸胆碱 (PC) 的调节。然而，我们的数据表明，根据治疗的不同，抑制可能导致 PC 增加或减少，从而限制了其作为反应的稳健生物标志物的用途。因此，本申请的目标是确定信号通路影响细胞代谢从而调节 PC 和其他含胆碱代谢物的机制。第二个目标是识别和验证对先前未探索的靶向疗法的反应的生物标志物。这项临床前研究将有助于更好地了解导致含胆碱代谢物变化的机制。因此，将有可能以更可靠、稳健和可预测的方式利用这些代谢物的调节来评估针对信号传导的疗法的反应。 MAPK 和 PI3K 信号传导可以通过影响参与胆碱代谢的酶来直接影响含胆碱的代谢物，也可以通过影响控制脂肪酸 (FA) 合成的脂肪酸合酶 (FASN) 来间接影响。因此，我们建议研究胆碱代谢和脂肪酸合成。我们将结合 1H、31P 和 13C MRS 并监测信号调节如何影响这两种代谢途径，从而影响含胆碱的代谢物。具体目标 1. 确定脂肪酸合成对胆碱代谢的影响。我们将首先确定 FASN 的抑制如何影响 FA 和胆碱代谢。我们将研究活细胞和提取物，并使用 1H、31P、13C MRS 来监测新陈代谢。具体目标 2. 确定信号通路与代谢之间的机制联系。使用与上述相同的方法，我们将监测 1) MAPK 抑制 2) PI3K 抑制和 3) 通过 HSP90 抑制多种信号通路对 FA 和胆碱代谢的影响。具体目标 3. 确认细胞中的机制发现可转化为体内肿瘤。将通过 1H、31P、13C MRS 对皮下肿瘤异种移植物进行研究，以确认特定目标 2 中的发现在体内成立。公共卫生相关性 磁共振波谱可用于无创监测针对特定致癌突变的新型癌症疗法的反应。然而，之前报道的治疗后磁共振可检测的代谢变化背后的确切机制尚不清楚。在此应用中，我们将研究这种联系，我们的研究将产生更稳健、可靠、可预测、无创、基于磁共振的肿瘤治疗反应指标，最终改善患者护理。