权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

GBM Avatar Screening Paradigm for Rational Pharmacokinomic Glioma Therapy

GBM Avatar 筛选范式用于合理的药代动力学神经胶质瘤治疗

基本信息

批准号：
10043740
负责人：
Christopher D Willey
金额：
$ 38.13万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10043740
关键词：
Archives Automobile Driving Brain Brain Glioblastoma Brain Neoplasms Cell physiology Cells Cessation of life Chemotherapy and/or radiation Classification Clinical Clinical Trials Consensus Cryopreservation DNA Sequence Alteration Data Diagnosis Drug Combinations Enzyme Kinetics Enzymes Excision FDA approved Freezing GTP-Binding Proteins Gene Activation Gene Expression Gene Expression Profile Genetic Genomics Glioblastoma Glioma Growth Harvest Human Immunocompromised Host Implant In Situ In Vitro Individual Malignant neoplasm of brain Measures Modality Modeling Molecular Profiling Mus Mutation Neoplasm Metastasis Newly Diagnosed Nude Mice Operative Surgical Procedures Patients Peptides Pharmaceutical Preparations Pharmacologic Substance Phosphorylation Phosphotransferases Process Protein Kinase Protein-Serine-Threonine Kinases Proteins Research Research Project Grants Resected Resistance Serial Passage Signal Pathway Stress Survival Rate System Testing The Cancer Genome Atlas Therapeutic Tissues Tumor Tissue Tyrosine Validation antitumor agent base blood-brain barrier permeabilization design effective therapy high throughput screening in vivo in vivo evaluation kinase inhibitor migration neoplastic cell novel drug class profiles in patients response screening small molecule inhibitor standard of care success tissue culture transcriptomics tumor tumor progression

项目摘要

This exploratory research project will utilize an alternative strategy that can be generally applied to select the most appropriate drug or drug combination to treat highly aggressive malignant brain tumors called glioblastoma multiforme (GBM). GBMs are diagnosed in over 17,000 patients each year and are essentially incurable. Despite over 75 years of research, our "best" standard of care therapies involve surgical resection, radiation and chemotherapy, but are not curative, providing only a 4% 5-year survival rate with an annual death toll of 12,000+. Most cellular functions are regulated inside all cells by kinases that enzymatically phosphorylate other proteins. Kinase-phosphorylated proteins are activated or suppressed to "drive" most cellular processes (e.g., proliferation, metastasis, survival) and to modulate cellular responses to therapies and other stresses. Small molecule inhibitors (SMIs) represent the fastest growing class of new drugs that block activities of cellular kinases, but are somewhat promiscuous in their effects. There are 518 known human protein kinases and many are either active in the cell (unregulated) or are activated by other kinases. Kinases are auto-phosphorylated or phosphorylated by other kinases serially to generate “cascades” down so called "signaling pathways". Inhibition of the right combination of kinases in certain signaling pathways will lead to death of tumor cells. We have a panel of human GBM Patient-Derived Xenolines (PDX) that were established in mice from surgical tumor tissues and were grown in the brains of mice, harvested and cryopreserved. Half (~27) have been extensively characterized genomically, transcriptomically and kinomically and form the “Reference Panel”; the other half (~24) are uncharacterized, at low passage and serve as our “Validation Panel”. These PDX will serve as patient "avatars" for drug selection. We will extract proteins from frozen tissues of six (6) of the low-passage Reference Panel PDX tumors to measure the ability of four (4) selected (blood-brain-barrier permeable) SMIs, to inhibit specific kinases that are enzymatically active in tumors. We will use ex vivo testing in which a small amount (1- 15g) of protein from each PDX is `spiked' with 1-20M of each SMI and analyzed in the PamStation-12 that can quantify enzymatic activity of 518 protein kinases and determine if a SMI "hits its target" or has “off-target” effects. The selection of potentially effective SMIs will be validated using low passage PDX for which the kinome profile will be determined, then matched to tumors in the Reference Panel. This will mimic the clinical situation in which a patient's tumor is kinomically profiled, and that profile matched to that of PDX that will have a previously defined SMI-responsiveness profile. We anticipate that the data developed in this exploratory research will demonstrate that this “avatar” approach can accurately predict potential therapeutics or combinations thereof for patients whose tumors resemble one or more PDX in the Reference and Validation Panels (~50+ PDX). We will use these data to support a R01-level application to validate our findings using orthotopic tumors in mice and in testing tumor tissues from GBM patients in anticipation of designing and conducting a pilot clinical trial.

这个探索性研究项目将利用一种可选择的策略，可以普遍应用于选择

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cancer Explant Models.

癌症外植体模型。

DOI：
10.1007/82_2019_157
发表时间：
2021
期刊：
Current topics in microbiology and immunology
影响因子：
0
作者：
Stackhouse CT;Gillespie GY;Willey CD
通讯作者：
Willey CD

Glioma stem cells and their roles within the hypoxic tumor microenvironment.

胶质瘤干细胞及其在缺氧肿瘤微环境中的作用。

DOI：
10.7150/thno.41692
发表时间：
2021
期刊：
Theranostics
影响因子：
12.4
作者：
Boyd NH;Tran AN;Bernstock JD;Etminan T;Jones AB;Gillespie GY;Friedman GK;Hjelmeland AB
通讯作者：
Hjelmeland AB