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: 8416461
• 负责人: PETER B BARKER
• 金额: $ 67.12万
• 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 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8416461
• 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; Critiques; Data; Development; Endogenous depression; Evaluation; Foundations; Funding; Gene Silencing; Glioblastoma; Glioma; Goals; Histone Acetylation; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone Deacetylation; Image; Imaging technology; Individual; Inositol; Institution; Life; Location; Magnetic Resonance Imaging; 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; Published Comment; Quality of life; Rattus; Recurrence; Regimen; Reproducibility; Research Project Grants; Resolution; Review Committee; 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; meetings; multimodality; pre-clinical; programs; public health relevance; 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，具有一致的致死性。 在癌发生过程中，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。 辛二酰苯胺异羟肟酸（SAHA）是一种口服有效的HDAC抑制剂。 这种药物不仅可以帮助控制肿瘤，还可以改变脑生物化学，以改善困扰许多GBM患者的抑郁症状。 一项由NCI资助的多机构GBM试验将SAHA与标准放化疗相结合，计划很快开放。 然而，缺乏可靠的生物标志物来预测早期反应严重阻碍了用HDAC抑制剂治疗GBM患者。 磁共振成像（MRI）是监测GBM治疗反应的标准工具。 虽然有用，但常规MRI具有缺点，包括难以区分真正的肿瘤进展与“假进展”，后者通常在放化疗完成后不久就出现。 MRI也可能不是评估新疗法的理想选择，其中许多疗法仅对一部分患者有帮助。 对于GBM，主要通过评估常规MRI上的肿瘤变化来评估治疗反应，因为重复手术活检侵入性太强，并且可能容易发生采样错误。 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。 虽然常规MRI可以检测肿瘤的大小和位置，但它无法检测这种类型的正常化。 我们建议通过使用磁共振光谱成像（MRSI）来填补这一空白，该成像在MRI扫描仪中使用特殊技术来测量癌细胞和正常大脑的代谢。 虽然MRSI并不新鲜，但由于分辨率差、扫描时间长以及难以与其他类型的脑部扫描整合，它尚未获得广泛的临床应用。 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图谱，并引入成像配准/分析程序，该程序将MRSI数据与临床上有用的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，可以在大多数机构中轻松实施。 建立 用于评估早期反应的可靠的MRSI代谢生物标志物在开发新的治疗方法，特别是那些不通过简单地杀死细胞而起作用的诸如SAHA的治疗方法中具有重要价值。 通过允许临床医生在短短一周的治疗中检测癌症代谢的正常化，注定要从治疗中受益的患者可以放心，而那些没有显示代谢反应的患者可以从无效的治疗中转换，而不会进一步浪费时间。 这显然是MRSI的一个高度创新的用途。 重要的是，除了监测肿瘤对SAHA治疗的反应外，我们基于MRI的工具将允许评估正常大脑的生化含量，从而可以间接监测受试者的生活质量。