Using Proton MRS to Predict Response of SAHA treatment in Glioblastoma

描述（由申请人提供）：胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤，尽管进行了积极的手术和辅助治疗，但它仍然是致命的。由于生存期短，在治疗早期确定治疗的价值是至关重要的。改进的早期预测评估将使神经肿瘤学家能够更快地调整或改变治疗方法，以最大限度地利用最有效的治疗方法。在癌变过程中，肿瘤抑制基因可以通过异常的组蛋白去乙酰化而沉默。这种表观遗传修饰已成为肿瘤治疗的重要靶点。亚甲基苯胺羟肟酸（SAHA）是一种口服有效的组蛋白去乙酰化酶（HDAC）活性抑制剂。临床效果可能包括肿瘤控制和可能改善情绪的大脑生化改变，纠正许多患者经历的抑郁症状。由于SAHA在恶性胶质瘤中的临床前结果很有希望，nci资助的成人脑肿瘤联盟（ABTC）目前正在对复发性GBM进行临床评估。此外，该组刚刚开展了新诊断的GBM联合替莫唑胺和放射治疗的I期评估。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肿瘤患者。由于侵入性活检的风险和不可靠的终点，频繁的组织学评估对GBM是不切实际的。另一个问题是，对SAHA治疗的反应与肿瘤再分化/细胞停滞有关，而不是肿瘤大小缩小，这限制了传统成像方法的使用。我们建议通过优化一种无创、纵向的MRS方法来填补这一空白，从而对生物标志物进行药效学评估。通过这种方式，我们可以在治疗过程中早期评估药物传递的有效性和治疗效果。在这里，我们的目标是开发一种基于磁共振成像的工具，帮助临床医生早期确定SAHA与替莫唑胺联合治疗的复发性GBM患者的价值，从而确定最有可能受益的患者。此外，我们将确定减少的肌醇和NAA是否是GBM患者情绪或抑郁改变的可靠生物标志物，SAHA治疗可能会减轻这种情况。因此，我们计划通过将MRS数据与精神病学评估相关联来评估复发性GBM患者情绪的潜在改善。通过允许临床医生调整SAHA治疗的剂量或寻求替代治疗，建立可靠的MRS生物标志物来评估早期反应，显然对胶质母细胞瘤患者的个性化管理具有价值。这样做的能力将是对现有技术（MRS）的高度创新的使用，这将在大多数机构中很容易实施。重要的是，我们基于核磁共振成像的工具将评估正常脑代谢的恢复，并间接监测受试者的生活质量。

DESCRIPTION (provided by applicant): Glioblastoma (GBM) is the most common primary brain tumor and is uniformly fatal despite aggressive surgical and adjuvant therapy. Since survival is short, it is critical to determine the value of therapy early during treatment. Improved early predictive assessment would allow neuro-oncologists to adjust or change treatment sooner to maximize use of the most effective therapy. During carcinogenesis, tumor suppressor genes can be silenced by aberrant histone deacetylation. This epigenetic modification has become an important target for tumor therapy. Suberoylanilide hydroxamic acid (SAHA) is an orally active, potent inhibitor of histone deacetylase (HDAC) activity. Clinical effects may include tumor control and cerebral biochemical alterations that may improve mood, correcting the depressive symptoms experienced by many of these patients. Clinical evaluation of SAHA in recurrent GBM is currently ongoing within the NCI-funded Adult Brain Tumor Consortium (ABTC) because of the promising preclinical results in malignant gliomas. In addition, a phase I evaluation in newly diagnosed GBM in combination with temozolomide and radiation therapy has just been opened by this group. The lack of reliable biomarkers to predict early response severely hampers the treatment of GBM tumor patients with HDAC inhibitors. Frequent histological evaluation is impractical for GBM due to the risks of invasive biopsies and unreliable endpoints. Another problem is that response to SAHA therapy is associated with tumor redifferentiation/cytostasis rather than tumor size reduction, limiting the use of traditional imaging methods. We propose to fill this void by optimizing an MRS method to pharmacodynamically assess biomarkers noninvasively and longitudinally. In this manner, we evaluate the efficacy of drug delivery and therapeutic effect early in the course of the treatment. Here our objective is to develop an MRS-based tool to aid clinicians in the early determination of the value of SAHA when administered to recurrent GBM patients treated with SAHA in combination with temozolomide, thereby identifying patients most likely to benefit. In addition, we will determine whether reduced inositol and NAA are reliable biomarkers of altered mood or depression in GBM patients, which may alleviated with SAHA treatment. Therefore, we plan to assess for potential improvement in the mood of recurrent GBM patients by correlating MRS data with a psychiatric evaluation. Establishing reliable MRS biomarkers to assess early response would clearly be of value in personalizing the management of glioblastoma patients by allowing clinicians to adjust the dose of SAHA treatment or seek alternative treatment. The ability to do this would be a highly innovative use of established technology (MRS) that would be readily implemented at most institutions. Importantly, our MRS-based tool will assess the restoration of normal brain metabolism, and indirectly monitor the subject's quality of life. PUBLIC HEALTH RELEVANCE: During carcinogenesis, tumor-suppressor genes can be silenced by aberrant histone deacetylation. This epigenetic modification has become an important target for tumor therapy. Vorinostat (SAHA, Zolinza; Merck & Co., Inc., Whitehouse Station, NJ) is an orally active, potent inhibitor of aberrant histone deacetylation activity that is currently being evaluated in glioblastoma patients. In this study, we will establish an important clinical tool to predict therapeutic response soon after treatment initiation. Our MRS- based tool will aid clinicians in early modification of SAHA treatment or in seeking alternative treatments in those with glioblastoma.