Pre-Clinical Novel Radiosensitizer Evaluation Program for Brain Tumors

项目摘要 在过去的十年里，在开发更有效的治疗方法方面基本上没有取得进展。 胶质母细胞瘤（GBM）。尽管积极的治疗与手术，放疗和替莫唑胺，中位数 GBM的生存期仅为一年多。虽然临床研究已经描述了重要的细胞- 由于放射的减少效应，主要的失效模式保持在照射的肿瘤体积内。的 与GBM局部进展相关的显著发病率代表了迫切的未满足的医疗需求。这 该项目将在GBM患者来源的异种移植（PDX）模型中评估5种新型放射/化学增敏药物 并将制定一个合理的框架，以确定最有希望的组合， 进行临床试验。这一框架可分为三套目标： 目的1：确定有效致敏剂的反应谱和潜在的预测生物标志物。 CTEP试剂的放射增敏作用将在体外和体内在广泛的一组实验中进行评价。 GBM PDX型号。结合已知的作用机制和药效学指标， 在这些研究中确定了缓解，将在以下研究中评价缓解的潜在机制生物标志物： 随后的体内研究。最终，这一目标的研究将提供对分数的理解， 肿瘤可能对特定治疗有反应，并可能确定潜在的生物标志物， 丰富最有可能从特定组合策略中获益的临床试验人群。 目的2：将关键药代动力学和药效学指标与药物疗效相关联。 全面了解药物在肿瘤和正常组织中的分布， 药效学效应对于确定哪些药物进入I期剂量寻求至关重要 研究和解释0期手术取样研究。这一目标的重点是确定关键参数， 例如血浆、正常脑和脑肿瘤中游离和结合药物暴露的决定因素， 将这些度量与有效放射增敏相关的剂量范围相关联。这些研究将使 根据现有的人体血浆药代动力学数据预测是否有效 放射增敏药物水平应该在脑中的人类肿瘤中可达到。 目的3：评价正常脑组织的放射增敏潜力。 放射治疗可导致显著的长期神经认知缺陷， 生活质量如果已知特定的放射增敏剂会增强这些不良反应，那么这将是至关重要的。 告知该策略的安全临床部署。因此，这方面的研究将评估药物/辐射 在小鼠模型中关于神经发生、神经炎症和认知的相互作用，以提供 了解放射增敏药物治疗如何影响脑照射的治疗窗。

PROJECT SUMMARY Essentially no progress has been made in the past decade in developing more effective therapies for glioblastoma (GBM). Despite aggressive treatment with surgery, radiation and temozolomide, the median survival for GBM remains just over one year. While clinical studies have delineated the important cyto- reductive effects of radiation, the predominant failure pattern remains within the irradiated tumor volume. The significant morbidity associated with local progression of GBM represents a pressing unmet medical need. This project will evaluate 5 novel radio/chemo-sensitizing drugs in GBM patient-derived xenograft (PDX) models and will develop a rational framework for identifying the most promising combinations that should be taken forward into clinical testing. This framework can be divided into three sets of Aims: Aim 1: Define the spectrum of response and potential predictive biomarkers for effective sensitizers. The radio-sensitizing effects of CTEP agents will be evaluated in vitro and in vivo across an extensive panel of GBM PDX models. In combination with known mechanisms of action and pharmacodynamic measures of response identified in these studies, potential mechanistic biomarkers of response will be evaluated in subsequent in vivo studies. Ultimately, the studies in this aim will provide both an understanding of the fraction of tumors likely to respond to a specific therapy and may identify potential biomarkers that could be used to enrich a clinical trial population most likely to benefit from a specific combination strategy. Aim 2: Correlate key pharmacokinetic and pharmacodynamic markers with drug efficacy. A comprehensive understanding of drug distribution into tumor and normal tissues, and associated pharmacodynamic effects, are critical for defining which drugs to move forward into Phase I dose-seeking studies and to interpret Phase 0 surgical sampling studies. The focus of this aim is to define key parameters, such as the determinants of free- and bound-drug exposure in plasma, normal brain and brain tumor, and to relate these metrics to a dose range associated with effective radiosensitization. These studies will enable predictions from readily available human pharmacokinetic data in plasma as to whether effective radiosensitizing drug levels should be achievable in human tumors in the brain. Aim 3: Evaluate the potential for radio-sensitization of normal brain tissues. Radiation therapy can cause significant long-term neuro-cognitive defects that dramatically impair patient quality of life. If a specific radiosensitizer is known to potentiate these adverse effects, then this would critically inform the safe clinical deployment of this strategy. Thus, studies in this aim will evaluate drug/radiation interactions with respect to neurogenesis, neuro-inflammation and cognition in mouse models to provide an understanding of how radiosensitizing drug therapy may influence the therapeutic window for brain irradiation.