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Quantitative MRSI to predict early response to SAHA therapy in new GBM management

定量 MRSI 可预测新 GBM 治疗中 SAHA 治疗的早期反应

基本信息

批准号：
9308872
负责人：
PETER B BARKER
金额：
$ 61.71万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-06 至 2018-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9308872
关键词：
Alanine Alternative Therapies Amino Acids Behavior Behavioral Biochemical Biochemistry Biological Markers Biopsy Brain Brain scan Cellular Metabolic Process Cerebrospinal Fluid Cerebrum Classification Clinic Clinical Clinical Trials Coupled Creatine Data Development Dimensions Foundations Funding Glioblastoma Glioma Goals Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Histone Deacetylation Image Image Analysis Imaging technology Individual Inositol Institution Location Magnetic Resonance Imaging Major Depressive Disorder Maps Measures Mental Depression Metabolic Metabolism Methods Modification Molecular Monitor Mood stabilizers Moods Motor Activity Multimodal Imaging N-acetylaspartate Neurocognition Neurons New Agents Newly Diagnosed Operative Surgical Procedures Oral Outcome Output Pathologic Patient Care Patient Self-Report Patients Pharmaceutical Preparations Primary Brain Neoplasms Procedures Prognostic Marker Quality of life Rattus Recurrence Regimen Reproducibility Research Project Grants Resolution Sampling Errors Scanning Schedule Site Social Interaction Surveys Techniques Technology Time Tissues Tumor Suppressor Genes Vorinostat base cancer imaging carcinogenesis cell killing chemoradiation clinical application clinical practice depressive symptoms image processing image registration imaging modality imaging study improved improved outcome increased appetite ineffective therapies inhibitor/antagonist innovation interest killings magnetic resonance spectroscopic imaging metabolic imaging novel therapeutics patient subsets pre-clinical predicting response programs public health relevance response restoration spectroscopic imaging temozolomide tool tool development treatment duration treatment response tumor tumor metabolism tumor progression vector wasting

项目摘要

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is the most common primary brain tumor and is uniformly fatal. During carcinogenesis, tumor suppressor genes are silenced by aberrant histone deacetylase (HDAC) activity. Reversing this modification has become a goal for tumor therapy. Suberoylanilide hydroxamic acid (SAHA) is an orally-active potent inhibitor of HDAC. This agent may not only help control tumors but also alter cerebral biochemistry to improve depressive symptoms afflicting many GBM patients. An NCI-funded multi-institutional trial for GBM combining SAHA with standard chemoradiation is scheduled to open soon. However, the lack of reliable biomarkers to predict early response severely hampers the treatment of GBM patients with HDAC inhibitors. Magnetic resonance imaging (MRI) is the standard tool for monitoring therapeutic response in GBMs. Although useful, conventional MRI has shortcomings including difficulty at distinguishing true tumor progression from "pseudo-progression" that is often seen soon after completion of chemoradiation. MRI may also not be ideal for evaluating new therapies, many of which help only a subset of patients. For GBMs, therapeutic response is mainly evaluated by assessing for tumor changes on conventional MRIs, since repeat surgical biopsy is too invasive and may be prone to sampling error. However, this is not ideal for evaluating response to SAHA since our preliminary data indicate that drug response is associated with redifferentiation rather than killing/shrinking tumors, which may normalize cancer cell metabolism. While conventional MRI detects tumor size and location, it cannot detect this type of normalization. We propose to fill this void by using MR spectroscopic imaging (MRSI), which uses special techniques in an MRI scanner to measure the metabolism of cancer cells as well as normal brain. While MRSI is not new, it has not gained widespread clinical use due to poor resolution, long scan times, and difficulty integrating with other types of brain scans. We propose to implement state-of-art MRSI technology that can rapidly generate metabolite maps of the entire brain coupled with introduction of an imaging registration/analysis program that combines MRSI data with other imaging studies in a clinically useful fashion. Our long-term goal is to develop MRSI into a practical clinical tool that can be readily implemented at most institutions. The establishment of reliable MRSI metabolic biomarkers to assess early response would be of great value in developing new treatments, especially those such as SAHA which do not work by simply killing cells. By allowing clinicians to detect normalization of cancer metabolism in as little as one week of therapy, patients destined to benefit from treatment may be reassured, while those not showing a metabolic response can be switched from an ineffective treatment without further wasting of time. This would clearly be a highly innovative use of MRSI. Importantly, in addition to monitoring tumor response to SAHA therapy, our MRSI-based tool will allow assessment of the biochemical content of normal brain, and may thus indirectly monitor the subject's quality-of-life.

描述(申请人提供)：多形性胶质母细胞瘤(GBM)是最常见的原发脑肿瘤，通常是致命的。在癌变过程中，肿瘤抑制基因被异常的组蛋白脱乙酰酶(HDAC)活性沉默。逆转这种修饰已成为肿瘤治疗的目标。琥珀酰苯胺异羟肟酸(SAHA)是一种具有口服活性的强效HDAC抑制剂。这种药物不仅有助于控制肿瘤，还可以改变大脑生化，以改善困扰许多GBM患者的抑郁症状。NCI资助的将SAHA与标准化疗放射相结合的GBM多机构试验计划很快开始。然而，缺乏可靠的生物标志物来预测早期反应，严重阻碍了HDAC抑制剂对GBM患者的治疗。磁共振成像(MRI)是监测肾小球基底膜瘤治疗反应的标准工具。虽然常规MRI有用，但它也有缺点，包括难以区分真正的肿瘤进展和“假进展”，后者通常在化疗结束后不久出现。MRI可能也不是评估新疗法的理想方法，因为许多新疗法只对一小部分患者有帮助。对于GEM，治疗反应主要是通过评估传统MRI上的肿瘤变化来评估的，因为重复手术活检太有侵入性，可能容易出现抽样错误。然而，这对于评估对SAHA的反应并不理想，因为我们的初步数据表明，药物反应与再分化有关，而不是与杀死/缩小肿瘤有关，后者可能会使癌细胞代谢正常化。虽然传统的MRI可以检测到肿瘤的大小和位置，但它无法检测到这种类型的正常化。我们建议通过使用磁共振光谱成像(MRSI)来填补这一空白，它使用MRI扫描仪中的特殊技术来测量癌细胞和正常大脑的新陈代谢。虽然MRSI并不新鲜，但由于分辨率低、扫描时间长以及难以与其他类型的脑部扫描相结合，它尚未得到广泛的临床应用。我们建议实施最先进的MRSI技术，该技术可以快速生成整个大脑的代谢物地图，并引入成像注册/分析程序，以临床有用的方式将MRSI数据与其他成像研究相结合。我们的长期目标是将MRSI发展成为一种实用的临床工具，可以很容易地在大多数机构实施。成立了可靠的MRSI代谢生物标记物用于评估早期反应将对开发新的治疗方法具有重要价值，特别是那些不能通过简单地杀死细胞来发挥作用的SAHA。通过允许临床医生在短短一周的治疗时间内检测到癌症代谢的正常化，注定要从治疗中受益的患者可能会放心，而那些没有表现出代谢反应的患者可以从无效的治疗中转换过来，而不会进一步浪费时间。这显然是MRSI的一种高度创新的使用。重要的是，除了监测肿瘤对SAHA治疗的反应外，我们基于磁共振成像的工具还将允许评估正常大脑的生化含量，从而可能间接监测受试者的生活质量。