MR Metabolic Imaging of Response to Targeted Therapies in GBM

GBM 靶向治疗反应的 MR 代谢成像

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：拟议研究的目标是开发并从机制上验证 MR 可检测的代谢生物标志物，以评估多形性胶质母细胞瘤 (GBM) 对针对致癌信号通路的新疗法的分子反应，这些信号通路在体内被激活此类病变。 GBM 患者的中位生存期不到 18 个月，新疗法对于改善预后至关重要。一种有前景的治疗方法是针对 PI3K/AKT/mTOR 通路，该通路在 88% 的 GBM 肿瘤中被激活。然而，此类新疗法的一个关键问题是药物活性常常导致肿瘤停滞，而目前的成像方法无法告知药物作用。拟议的研究将使用以前未探索过的方法来解决这一未满足的需求。 PI3K/AKT/mTOR 信号传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 PC 水平（可通过 1H MRS 监测总胆碱代谢物 (tCho) 进行检测）和超极化乳酸水平（可通过使用 13C MRS 监测超极化丙酮酸代谢进行检测）可以作为 PI3K/AKT/mTOR 的关联下游生物标志物信号传导并通过抑制该信号传导的药物提供药物靶标调节的代谢读数。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，并验证它们在检测新兴 PI3K/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，MR 技术将应用于参与最先进临床试验的 GBM 患者。目标 1. 应用 31P、1H 和超极化 13C MRS 以及补充生物测定来对照和 PI3K/AKT/mTOR 抑制剂处理的具有不同遗传背景的 GBM 细胞，以验证 PC、tCho 和超极化乳酸作为分子反应的生物标志物来治疗。目标 2. 应用 1H MRSI、超极化 13C MRSI 和补充生物测定来对照和 PI3K/AKT/mTOR 抑制剂治疗的具有不同遗传背景的大鼠原位 GBM 肿瘤，以验证 tCho 和超极化乳酸作为分子反应生物标志物的作用进行体内治疗。目标 3. 将 1H MRSI 和超极化 13C MRSI 应用于正在接受标准护理放疗 (RT) 和替莫唑胺联合 PI3K/AKT/mTOR 抑制剂治疗的新诊断 GBM 患者，以验证体内 tCho 的作用和乳酸作为治疗反应的生物标志物。拟议的研究将产生一种成像方法，可以为药物输送和分子反应提供信息。它将能够对肿瘤部位的药物作用进行纵向监测，并将提供优化治疗方案的工具，从而为 GBM 患者提供更加个性化的护理并改善预后。