Admin-Core-001

胶质母细胞瘤（GBM）有效疗法的开发一直令人难以置信的烦恼，十多年来没有新药批准。任何一个GBM患者的治疗耐药性可能与多种因素有关，包括肿瘤细胞广泛浸润到邻近脑中、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，我们在过去十年中建立了一支高效的多学科科学团队，拥有系统生物学，药理学，肿瘤生物学和GBM动物模型的专业知识。在拟议的U19中心申请中，我们将整合这个已建立的跨学科转化科学团队与放射和医学肿瘤学，神经外科和神经放射学的医生科学家，共同致力于将新的治疗策略转化为GBM患者的高效疗法。受损的DDR使得肿瘤发生所需的基因组不稳定性成为可能，并且肿瘤和正常组织之间DDR功能的差异提供了使用放射疗法或遗传毒性药物作为抗癌疗法的基本原理。肿瘤中DDR的额外靶向药理学破坏可显著增强这些细胞毒性疗法的功效并拓宽治疗窗。在这种情况下，我们与多家制药公司进行了广泛的合作，以评估各种小分子DDR抑制剂，并开发了重要的初步数据，证明这些药物与常规用于GBM的放射或烷基化化疗联合使用时具有深刻的组合疗效。因此，我们中心的最初重点是优化DDR抑制剂与细胞毒性疗法联合用于GBM的临床部署。药理学核心将支持动物模型和人体样本的药代动力学（PK）和药效学（PD）评估，我们的治疗评估核心将支持新治疗策略的临床前和临床测试。该项目和核心团队将密切合作，以实现该中心的目标，并在该中心和整个更广泛的胶质瘤治疗网络（GTN）的这种合作努力将由行政核心协调。

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.