Center of Innovation for Brain Tumor Therapeutics

项目描述/摘要-总体 胶质母细胞瘤（GBM）的有效治疗方法的开发一直令人难以置信的烦恼，没有新药 十多年的批准。任何一个GBM患者的治疗耐药可能与多种因素有关 包括广泛的肿瘤细胞浸润到邻近的脑中，肿瘤细胞群的分子异质性， 和药物分布的异质性。为了理解和克服这些挑战，我们建立了一个 在过去十年中，我们拥有一支高效率的多学科科学团队，其专业知识跨越了各个系统 生物学、药理学、肿瘤生物学和GBM的动物模型。在建议的U19中心应用程序中，我们 将整合这一建立跨学科的转化科学团队与医生的科学家在辐射 以及肿瘤内科、神经外科和神经放射科，共同致力于将新的治疗方法 GBM患者的高效治疗策略。 受损的DDR使肿瘤发生所需的基因组不稳定性，以及DDR的差异 肿瘤和正常组织之间的功能性提供了使用放射治疗的基本原理， 基因毒性药物作为抗癌疗法。肿瘤中DDR的其他靶向药理学破坏可以 显著增强这些细胞毒性疗法的功效并拓宽治疗窗。在这一背景下， 我们与多家制药公司广泛合作，评估各种小分子 DDR抑制剂，并已开发出重要的初步数据，证明了深刻的组合功效 这些药物与常规用于GBM的放疗或烷化剂化疗联合使用时，因此 我们中心最初的重点是优化DDR抑制剂与细胞毒性药物联合的临床应用。 治疗GBM。药理学核心将支持药代动力学（PK）和药效学（PD） 在动物模型和人体样本中进行评估，我们的治疗评估核心将支持临床前 和新治疗策略的临床试验。项目和核心团队将密切合作 为了实现中心的目标，以及中心内部和更广泛的合作努力， 神经胶质瘤治疗网络（GTN）将由行政核心协调。

PROJECT DESCRIPTION/ABSTRACT – OVERALL The development of effective therapies for glioblastoma (GBM) has been incredibly vexing with no new drug approvals in over a decade. Therapeutic resistance in any one patient with GBM can be related to multiple factors including extensive tumor cell infiltration into adjacent brain, molecular heterogeneity of tumor cell populations, and heterogeneity of drug distribution. In order to understand and overcome these challenges, we have built a highly productive, multi-disciplinary scientific team over the past decade with expertise spanning systems biology, pharmacology, tumor biology, and animal models of GBM. In the proposed U19 Center application, we will integrate this established cross-disciplinary translational science team with physician scientists in radiation and medical oncology, neurosurgery and neuroradiology with a collective focus of translating novel therapeutic strategies into highly effective therapies for patients with GBM. Impaired DDR enables the genomic instability required for tumorigenesis, and differences in DDR functionality between tumor and normal tissue provides the fundamental rationale for using radiation therapy or genotoxic drugs as anti-cancer therapies. Additional targeted pharmacologic disruption of DDR in tumors can markedly enhance the efficacy of these cytotoxic therapies and widen the therapeutic window. In this context, we have collaborated extensively with multiple pharmaceutical companies to evaluate various small molecule DDR inhibitors and have developed significant preliminary data demonstrating profound combinatorial efficacy for these drugs when combined with radiation or alkylating chemotherapy routinely used for GBM. Thus, the initial focus for our Center is to optimize the clinical deployment of DDR inhibitors in combination with cytotoxic therapies for GBM. A Pharmacology Core will support both pharmacokinetic (PK) and pharmacodynamic (PD) evaluations in animal models and human samples, and our Therapy Evaluation Core will support both pre-clinical and clinical testing of novel therapeutic strategies. The Project and Core teams will work in close collaboration to accomplish the goals of the Center, and this collaborative effort within the Center and across the broader Glioma Therapeutics Network (GTN) will be coordinated by the Administrative Core.