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Center of Innovation for Brain Tumor Therapeutics

脑肿瘤治疗创新中心

基本信息

批准号：
10492762
负责人：
Ranjit Bindra
金额：
$ 118.77万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10492762
关键词：
Address Adjuvant Aftercare Animal Model Biological Assay Biopsy Biotechnology Brain Brain Neoplasms Clinic Clinical Collaborations Communities Cytotoxic Chemotherapy DNA Damage Data Development Drug Exposure Drug Targeting Evaluation Excision Fostering Funding Genomic Instability Glioblastoma Glioma Goals Gold Grant Heterogeneity Human Impairment Infiltration Investigation Laboratories Leadership Manuscripts Medical Oncology Modeling Molecular New Drug Approvals Normal tissue morphology Operative Surgical Procedures Patients Pharmaceutical Preparations Pharmacologic Substance Pharmacology Physicians Population Heterogeneity Preclinical Testing Publishing Radiation Radiation Oncology Radiation therapy Research Risk Sampling Scientist Structure Systems Biology Testing Therapeutic Therapy Evaluation Translating Translational Research Treatment Failure Tumor Biology Tumor Tissue United States National Institutes of Health Work animal tissue cancer therapy cerebral microvasculature chemotherapy clinical development clinical translation cohort combinatorial drug distribution drug efficacy effective therapy genotoxicity human tissue inhibitor innovation member multidisciplinary neoplastic cell neuro-oncology neurosurgery novel therapeutic intervention novel therapeutics outreach patient derived xenograft model pharmacokinetics and pharmacodynamics pre-clinical research clinical testing response small molecule temozolomide therapeutically effective therapy resistant tool translational study tumor tumor heterogeneity tumorigenesis

项目摘要

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.

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。