Center of Innovation for Brain Tumor Therapeutics

项目说明/摘要--总体 在没有新药的情况下，胶质母细胞瘤(GBM)的有效治疗方法的发展一直令人难以置信地烦恼。 十多年来的批准。任何一位GBM患者的治疗耐药可能与多个因素有关 包括肿瘤细胞广泛侵入邻近脑组织，肿瘤细胞群体的分子异质性， 以及药物分布的异质性。为了理解和克服这些挑战，我们建立了一个 在过去十年中，高效、多学科的科学团队拥有跨越系统的专业知识 基底膜的生物学、药理学、肿瘤生物学和动物模型。在建议的U19中心申请中，我们 将把这个已建立的跨学科转换科学团队与辐射领域的内科科学家整合在一起 以及内科肿瘤学、神经外科和神经放射学，共同专注于翻译新的治疗方法 对GBM患者进行高效治疗的策略。 DDR受损使肿瘤发生所需的基因组不稳定，以及DDR的差异 肿瘤和正常组织之间的功能提供了使用放射治疗或 基因毒性药物作为抗癌疗法。肿瘤中DDR的额外靶向药物干扰可以 显著提高了这些细胞毒疗法的疗效，拓宽了治疗窗口。在这方面， 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，证明了深刻的联合疗效 对于这些药物，当与放射或烷化化疗相结合时，通常用于GBM。因此， 我们中心最初的重点是优化DDR抑制剂与细胞毒联合使用的临床部署 GBM的治疗方法。药理学核心将同时支持药代动力学(PK)和药效学(PD) 在动物模型和人类样本中进行评估，我们的治疗评估核心将支持临床前 以及对新的治疗策略的临床测试。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范围内的这种协作努力 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.