Center of Innovation for Brain Tumor Therapeutics

脑肿瘤治疗创新中心

基本信息

批准号：
10704623
负责人：
Ranjit Bindra
金额：
$ 199.92万
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/10704623
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 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 Preclinical Testing Productivity Publishing Radiation Radiation Oncology Radiation therapy Recurrence 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 pharmacologic pre-clinical research clinical testing response routine therapy 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.

项目描述/摘要 - 总体胶质母细胞瘤（GBM）的有效疗法的发展令人难以置信十多年来的批准。任何一个GBM患者的治疗性抗性都可能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，我们建立了一个在过去的十年中，具有跨系统的专业知识，高产，多学科的科学团队 GBM的生物学，药理学，肿瘤生物学和动物模型。在拟议的U19中心申请中，我们将把这个既定的跨学科翻译科学团队与辐射的物理科学家整合在一起以及医学肿瘤学，神经外科和神经放射学，集体翻译新疗法的重点针对GBM患者的高效疗法的策略。受损的DDR使肿瘤发生所需的基因组不稳定性以及DDR的差异肿瘤和正常组织之间的功能性提供了使用放射疗法或遗传毒性药物作为抗癌疗法。肿瘤中DDR的其他靶向药物结肠破坏可以显着提高了这些细胞毒性疗法的效率并扩大了治疗窗口。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抑制剂并已开发出明显的初步数据，证明了深远的组合效率对于这些药物，当与GBM通常使用的放射线或烷基化化学疗法结合使用时。那，我们中心的最初重点是优化DDR抑制剂的临床部署，并结合细胞毒性。 GBM的疗法。药理学核心将支持药代动力学（PK）和药效学（PD）在动物模型和人类样本中的评估以及我们的治疗评估核心将支持这两个前临床前和新型治疗策略的临床测试。该项目和核心团队将密切合作实现中心的目标，以及中心内部和整个更广泛的合作努力胶质瘤治疗网络（GTN）将由行政核心协调。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

MDM2 Inhibition in the Treatment of Glioblastoma: From Concept to Clinical Investigation.

DOI：
10.3390/biomedicines11071879
发表时间：
2023-07-02
期刊：
Biomedicines
影响因子：
4.7
作者：
通讯作者：

Pharmacokinetics of panobinostat: Inter-species difference in metabolic stability.

帕比司他的药代动力学：代谢稳定性的种间差异。

DOI：
10.1124/jpet.123.002051
发表时间：
2024
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
0
作者：
Zhang,Wenqiu;Oh,Ju-Hee;Zhang,Wenjuan;Aldrich,CourtneyC;Sirianni,RachaelW;Elmquist,WilliamF
通讯作者：
Elmquist,WilliamF