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

• 批准号: 8890122
• 负责人: PETER B BARKER
• 金额: $ 63.27万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-06 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8890122
• 关键词: Alanine; Alternative Therapies; Amino Acids; Arts; Behavior; Behavioral; Biochemical; Biochemistry; Biological Markers; Biopsy; Brain; Brain scan; Cerebrospinal Fluid; Cerebrum; Classification; Clinic; Clinical; Clinical Trials; Coupled; Creatine; Data; Development; Foundations; Funding; Gene Silencing; Glioblastoma; Glioma; Goals; Health; Histone Acetylation; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone Deacetylation; Image; Imaging technology; Individual; Inositol; Institution; Life; Location; Magnetic Resonance Imaging; Major Depressive Disorder; Maps; Measures; Mental Depression; Metabolic; Metabolism; Methods; Modification; Molecular; Monitor; Mood stabilizers; Moods; Motor Activity; N-acetylaspartate; Neurocognition; Neurons; New Agents; Newly Diagnosed; Operative Surgical Procedures; 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; Therapeutic; Time; Tissues; Tumor Suppressor Genes; Vorinostat; Work; base; cancer cell; carcinogenesis; cell killing; chemoradiation; clinical application; clinical practice; depressive symptoms; image processing; image registration; imaging modality; improved; increased appetite; inhibitor/antagonist; innovation; interest; killings; magnetic resonance spectroscopic imaging; multimodality; pre-clinical; programs; response; restoration; spectroscopic imaging; temozolomide; tool; tool development; treatment duration; tumor; tumor metabolism; tumor progression; vector; wasting

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（由申请人提供）：多形性胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤，具有致命性。在癌变过程中，肿瘤抑制基因被异常的组蛋白去乙酰化酶（HDAC）活性沉默。逆转这种修饰已经成为肿瘤治疗的目标。亚甲基苯胺羟肟酸（SAHA）是一种有效的口服HDAC抑制剂。这种药物不仅可以帮助控制肿瘤，还可以改变大脑生物化学，以改善困扰许多GBM患者的抑郁症状。一项nci资助的GBM联合SAHA和标准放化疗的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使用HDAC抑制剂治疗GBM患者。磁共振成像（MRI）是监测GBMs治疗反应的标准工具。传统的MRI虽然有用，但也有缺点，包括难以区分真正的肿瘤进展和通常在放化疗完成后不久出现的“假进展”。核磁共振成像也可能不是评估新疗法的理想方法，其中许多疗法只能帮助一小部分患者。对于GBMs，主要通过评估常规mri上的肿瘤变化来评估治疗反应，因为重复手术活检的侵入性太强，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，而不是杀死/缩小肿瘤，这可能使癌细胞代谢正常化。而传统的MRI检测肿瘤的大小和位置，它不能检测到这种归一化。我们建议用核磁共振光谱成像（MRSI）来填补这一空白，它使用核磁共振扫描仪中的特殊技术来测量癌细胞和正常大脑的代谢。虽然核磁共振成像并不新鲜，但由于分辨率差、扫描时间长、难以与其他类型的脑部扫描相结合，它尚未获得广泛的临床应用。我们建议采用最先进的核磁共振成像技术，该技术可以快速生成整个大脑的代谢物图谱，同时引入一种成像注册/分析程序，将核磁共振成像数据与其他成像研究结合起来，以一种临床有用的方式。我们的长期目标是发展核磁共振成像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。建立