Admin-Core-001

管理核心-001

• 批准号: 10707742
• 负责人: Ranjit Bindra
• 金额: $ 6.2万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707742
• 关键词: Admin; Core; 001

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.

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地烦恼，十多年来没有新药获批。任何一名GBM患者的治疗耐药可能与多种因素有关，包括肿瘤细胞向邻近脑的广泛浸润、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，他们的专业知识涵盖系统生物学、药理学、肿瘤生物学和GBM动物模型。在U19中心的申请中，我们将把这个已经建立的跨学科转化科学团队与放射和内科肿瘤学、神经外科和神经放射学的内科科学家结合起来，共同致力于将新的治疗策略转化为GBM患者的高效治疗方法。受损的DDR使肿瘤发生所需的基因组不稳定，肿瘤和正常组织之间DDR功能的差异为使用放射治疗或基因毒性药物作为抗癌治疗提供了基本依据。在肿瘤中对DDR进行额外的靶向药物破坏可以显著提高这些细胞毒疗法的疗效，并扩大治疗窗口。在此背景下，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，并获得了重要的初步数据，证明这些药物与常规用于GBM的放疗或烷基化化疗联合使用时具有深远的组合疗效。因此，我们中心最初的重点是优化DDR抑制剂与细胞毒疗法联合治疗GBM的临床应用。药理学核心将支持动物模型和人类样本的药代动力学（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。项目和核心团队将密切合作，以实现中心的目标，中心内部和更广泛的胶质瘤治疗网络（GTN）的合作努力将由行政核心协调。