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: 7923182
• 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/7923182
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affect; Animals; Biological Markers; Biometry; Cell Extracts; Cells; Choline; Clinical Trials; Collaborations; Congenital Abnormality; Data; Development; Drug Delivery Systems; Electronics; Enzymes; Equipment; Fatty Acids; Fatty-acid synthase; Goals; Head; Heat-Shock Proteins 90; Investigation; Kinetics; Label; Lead; Life; Link; Lipids; 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; 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; imaging modality; improved; in vivo; neoplastic cell; novel; pre-clinical research; public health relevance; 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）：新型的抗癌疗法越来越涉及靶向导致造成癌症的分子遗传异常。然而，对这种疗法的反应通常与肿瘤停滞有关，而不是收缩，这限制了传统成像方法的效用以监测早期反应。我们的长期目标是开发非侵入性，局部磁共振（MR）的方法，以检测分子对靶向治疗的反应。我们已经表明，通过有丝分裂原活化蛋白激酶（MAPK）和磷脂酰肌醇3-激酶（PI3K）途径抑制信号传导会导致MR光谱法（MRS）可检测胆碱含胆碱的代谢产物的调节。但是，我们的数据表明，取决于治疗，抑制作用可能导致PC的增加或减少，从而将其用作强大的反应生物标志物。因此，该应用的目的是确定信号通路影响细胞代谢的机制，从而导致PC和其他含胆碱的代谢产物的调节。第二个目标是识别和验证对先前未开发的靶向疗法的反应生物标志物。这项临床前研究将使人们更好地了解导致含胆碱代谢物的变化的机制。结果，可以以更可靠，健壮和可预测的方式在这些代谢产物中使用调制，以评估对靶向信号的疗法的反应。 MAPK和PI3K信号传导可以通过影响脂肪酸合酶（FASN）来影响与胆碱代谢相关的酶，或与脂肪酸合成（FA）合成，直接影响含胆碱的代谢产物。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，并监视信号传导的调节如何影响两种代谢途径，从而影响含有胆碱的代谢物。具体目的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监测代谢。具体目的2。确定信号通路和代谢之间的机械联系。使用与上述相同的方法，将监测1）MAPK抑制的FA和胆碱代谢的影响2）PI3K抑制和3）通过HSP90抑制多个信号通路。具体目的3。确认细胞中的机械发现转化为体内肿瘤。皮下肿瘤异种移植物将通过1H，31p，13c MRS研究，以确认特定AIM 2中提出的发现在体内保持真实。公共卫生相关性磁共振光谱可用于非侵入性监测对针对特定致癌突变的新型癌症疗法的反应。然而，尚不清楚治疗后先前报道的可检测代谢变化背后的确切机制尚不清楚。在此应用中，我们将研究此链接，我们的研究将导致更健壮，可靠，可预测的，无创，基于磁共振的基于肿瘤对治疗的反应指标，最终改善患者护理。