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.

十多年来，胶质母细胞瘤（GBM）的有效疗法的发展令人难以置信。任何一个GBM患者的治疗性耐药性都与多种因素有关，包括广泛的肿瘤细胞浸润到相邻大脑中，肿瘤细胞群体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个高产，多学科的科学团队，其专业知识跨越了系统生物学，药理学，肿瘤生物学和GBM的动物模型。在拟议的U19中心应用中，我们将将这一既定的跨学科转化科学团队与放射线和医学肿瘤学，神经外科和神经放射学方面的医师科学家相结合，并集体将新颖的治疗策略转化为GBM患者的高效疗法。受损的DDR可实现肿瘤发生所需的基因组不稳定性，而肿瘤和正常组织之间的DDR功能差异为使用放射治疗或遗传毒性药物作为抗癌疗法提供了基本原理。 DDR在肿瘤中的其他靶向药理学破坏可以显着增强这些细胞毒性疗法的功效，并扩大治疗窗口。在这种情况下，我们已经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，并制定了重要的初步数据，这些数据与辐射或烷基化的化学疗法相结合时，证明了这些药物的深刻组合功效，通常用于GBM。因此，我们中心的最初重点是优化DDR抑制剂与GBM的细胞毒性疗法的临床部署。药理学核心将支持动物模型和人类样品中的药代动力学（PK）和药效学（PD）评估，我们的治疗评估核心将支持新型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中心的目标，并且该中心内部以及整个更广泛的神经胶质瘤治疗网络（GTN）将由行政核心协调。