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）有效疗法的开发非常令人烦恼，十多年来没有新药获得批准。任何一名 GBM 患者的治疗耐药可能与多种因素有关，包括肿瘤细胞广泛浸润邻近大脑、肿瘤细胞群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，我们在过去十年中建立了一支高效、多学科的科学团队，其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。在拟议的 U19 中心申请中，我们将把这个已建立的跨学科转化科学团队与放射和肿瘤医学、神经外科和神经放射学领域的医师科学家整合起来，共同致力于将新颖的治疗策略转化为针对 GBM 患者的高效疗法。 DDR 受损会导致肿瘤发生所需的基因组不稳定性，而肿瘤和正常组织之间 DDR 功能的差异为使用放射疗法或基因毒性药物作为抗癌疗法提供了基本原理。对肿瘤中 DDR 进行额外的靶向药理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。在此背景下，我们与多家制药公司广泛合作，评估各种小分子 DDR 抑制剂，并开发了重要的初步数据，证明这些药物与常规用于 GBM 的放疗或烷化化疗联合使用时具有深远的组合功效。因此，我们中心的最初重点是优化 DDR 抑制剂与 GBM 细胞毒疗法相结合的临床部署。药理学核心将支持动物模型和人体样本中的药代动力学 (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。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) 内的这种协作努力将由行政核心进行协调。