MR Metabolic Imaging of Response to Targeted Therapies in GBM

GBM 靶向治疗反应的 MR 代谢成像

• 批准号: 8330237
• 负责人: SARAH J. NELSON
• 金额: $ 58.69万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-08 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8330237
• 关键词: Address; Affect; Biological; Biological Assay; Biological Markers; Biological Models; Caring; Cells; Choline; Choline Kinase; Clinical Trials; Coin; Drug Delivery Systems; Drug effect disorder; Enzymes; Genetic; Glioblastoma; Glucose; Goals; Image; Individual; Lactate Dehydrogenase; Lead; Lesion; Link; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Malignant Neoplasms; Metabolic; Metabolism; Molecular; Monitor; Motivation; Newly Diagnosed; Oncogenic; Outcome; PI3K/AKT; Pathway interactions; Patient Care; Patients; Pharmaceutical Preparations; Phosphorylcholine; Pyruvate; Pyruvate Metabolism Pathway; Quality of life; Radiation therapy; Rattus; Reading; Regimen; Reporting; Research; Role; Signal Pathway; Signal Transduction; Site; Techniques; Therapeutic; cancer type; human FRAP1 protein; imaging modality; improved; in vivo; inhibitor/antagonist; mTOR Inhibitor; novel; pre-clinical; response; standard of care; temozolomide; tool; tumor

DESCRIPTION (provided by applicant): The goal of the proposed research is to develop and mechanistically validate MR-detectable metabolic biomarkers in order to evaluate the molecular response of glioblastoma multiforme (GBM) to novel therapies that target oncogenic signaling pathways, which are activated within such lesions. The median survival for GBM patients is less than eighteen months, and new therapies are essential to improve outcome. A promising therapeutic approach is to target the PI3K/AKT/mTOR pathway, which is activated in 88% of GBM tumors. However, a critical issue with such novel treatments is that drug activity often results in tumor stasis, and current imaging methods do not inform upon drug action. The proposed research will use a previously unexplored approach to address this unmet need. PI3K/AKT/mTOR signaling modulates the conversion of pyruvate into lactate as well as the synthesis of phosphocholine (PC). We hypothesize that levels of PC, detectable by monitoring total choline-containing metabolites (tCho) by 1H MRS, and levels of hyperpolarized lactate, detectable by monitoring hyperpolarized pyruvate metabolism using 13C MRS, can serve as linked downstream biomarkers of PI3K/AKT/mTOR signaling and provide a metabolic read-out of drug-target modulation by agents that inhibit this signaling. Our strategy in the proposed research is first to use non-invasive MR techniques in tumor model systems to monitor changes in tCho and hyperpolarized lactate and to validate their role in detecting molecular response to emerging PI3K/AKT/mTOR inhibitors. After confirming the biological significance of these parameters in a pre-clinical setting, MR techniques will be applied to patients with GBM who are participating in state of the art clinical trials. Aim 1. To apply 31P, 1H and hyperpolarized 13C MRS as well as complementary biological assays to control and PI3K/AKT/mTOR inhibitor-treated GBM cells with different genetic backgrounds in order to validate PC, tCho and hyperpolarized lactate as biomarkers of molecular response to therapy. Aim 2. To apply 1H MRSI, hyperpolarized 13C MRSI and complementary biological assays to control and PI3K/AKT/mTOR inhibitor-treated rat orthotopic GBM tumors with different genetic backgrounds in order to validate the role of tCho and hyperpolarized lactate as biomarkers of molecular response to therapy in vivo. Aim 3. To apply 1H MRSI and hyperpolarized 13C MRSI to patients with newly diagnosed GBM who are being treated with standard of care radiotherapy (RT) and temozolomide in combination with PI3K/AKT/mTOR inhibitors in order to validate the role of in vivo tCho and lactate as biomarkers of response to therapy. The proposed research will result in an imaging method that can inform on drug delivery and molecular response. It will enable longitudinal monitoring of drug action at the tumor site and will provide a tool to optimize therapeutic regimens, resulting in more personalized care and improved outcome for GBM patients.

描述（由申请方提供）：拟定研究的目的是开发和机械验证MR可检测的代谢生物标志物，以评价多形性胶质母细胞瘤（GBM）对靶向致癌信号通路的新型疗法的分子反应，这些通路在此类病变中被激活。 GBM患者的中位生存期不到18个月，新的治疗方法对改善预后至关重要。一种有希望的治疗方法是靶向PI 3 K/AKT/mTOR通路，该通路在88%的GBM肿瘤中被激活。然而，这种新型治疗的一个关键问题是药物活性通常导致肿瘤停滞，并且目前的成像方法不能提供药物作用的信息。拟议的研究将使用以前未探索的方法来解决这一未满足的需求。 PI 3 K/AKT/mTOR信号转导调节丙酮酸转化为乳酸以及磷酸胆碱（PC）的合成。我们假设，通过1H MRS监测总含胆碱代谢物（tCho）可检测到的PC水平和通过13 C MRS监测超极化丙酮酸代谢可检测到的超极化乳酸水平可以作为PI 3 K/AKT/mTOR信号传导的相关下游生物标志物，并通过抑制该信号传导的药物提供药物靶点调节的代谢读数。 我们在拟议研究中的策略是首先在肿瘤模型系统中使用非侵入性MR技术来监测tCho和超极化乳酸的变化，并验证它们在检测对新兴PI 3 K/AKT/mTOR抑制剂的分子反应中的作用。在临床前环境中确认这些参数的生物学意义后，将对参与最新技术水平临床试验的GBM患者应用MR技术。 目标1.应用31 P、1H和超极化13 C MRS以及补充生物学测定法对对照和PI 3 K/AKT/mTOR修饰物处理的具有不同遗传背景的GBM细胞进行检测，以验证PC、tCho和超极化乳酸作为对治疗的分子应答的生物标志物。 目标2.将1H MRSI、超极化13 C MRSI和补充生物学测定应用于对照和PI 3 K/AKT/mTOR介导物治疗的具有不同遗传背景的大鼠原位GBM肿瘤，以验证tCho和超极化乳酸作为体内治疗分子应答的生物标志物的作用。 目标3。将1H MRSI和超极化13 C MRSI应用于正在接受标准放疗（RT）和替莫唑胺联合PI 3 K/AKT/mTOR抑制剂治疗的新诊断GBM患者，以验证体内tCho和乳酸作为治疗反应生物标志物的作用。 拟议的研究将产生一种成像方法，可以告知药物输送和分子反应。它将能够纵向监测肿瘤部位的药物作用，并将提供优化治疗方案的工具，从而为GBM患者提供更个性化的护理和改善的结果。