Brain Tumor Animal Therapeutics Core

脑肿瘤动物治疗核心

• 批准号: 8763760
• 负责人: Howard Fine
• 金额: $ 64.87万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8763760
• 关键词: Alkylating Agents; Animal Experiments; Animal Model; Animals; Area; Behavior; Benzodiazepine Receptor; Biological; Biological Process; Biology; Biopsy; Biotechnology; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Breeding; CC-5013; Cancer cell line; Categories; Cell Line; Cell Proliferation; Cell Survival; Cells; Characteristics; Clinic; Clinical; Clinical Drug Development; Clinical Investigator; Clinical Trials; Clinical Trials Design; Collaborations; Communities; Complex; Convection; Cytostatics; DNA; Data; Development; Developmental Therapeutics Program; Diagnostic; Dose; Drug Delivery Systems; Drug Targeting; Drug effect disorder; Educational process of instructing; Evaluation; Extramural Activities; Freezing; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Generations; Genetic; Genetic Vectors; Glioma; Growth; Human; Image; In Vitro; Institution; Intracarotid; LY317615; Label; Laboratories; Leadership; Ligand Binding; Magnetic Resonance Imaging; Malignant Glioma; Methods; Microarray Analysis; Mission; Modeling; Molecular Profiling; Monitor; Multi-Drug Resistance; Mus; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; New Agents; Operative Surgical Procedures; Pathway interactions; Patients; Pattern; Peripheral; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Positron-Emission Tomography; Preclinical Drug Evaluation; Preparation; Private Sector; Progression-Free Survivals; Property; Protamine Sulfate; Protective Agents; Proteins; RNA; Radiation-Sensitizing Agents; Randomized; Rattus; Real-Time Systems; Research; Research Design; Research Personnel; Resistance; Resources; Role; Sampling; Schedule; Science; Serum; Serum Markers; Services; Specimen; Stem Cell Factor; Stem cells; Surrogate Markers; Talampanel; Technology; Testing; Therapeutic; Time; Tissues; Toxicology; Tumor Cell Line; Tumor Stem Cells; Tumor Tissue; United States National Institutes of Health; Work; Xenograft procedure; ZD-6474; angiogenesis; antitumor agent; antitumor drug; base; cancer stem cell; cytotoxic; design; expectation; ferumoxides; genetic profiling; glioma cell line; human disease; implantation; in vivo; inhibitor/antagonist; mouse model; neoplastic cell; neuro-oncology; neurotoxicity; notch protein; novel; pre-clinical; preclinical evaluation; programs; relating to nervous system; repository; research study; response; screening; stathmin; subcutaneous; success; tumor; tumor progression; vasculogenesis

Under the leadership of Dr Fine,the NOB Lab has collaborated with pharmaceutical companies and academic institutions,and the NCI Developmental Therapeutics Program in the preclinical and clinical development of a number of new anti-glioma agents.The first step in the development pipeline is screening of the agent through the ABTC.The ABTC provides the professional service for screening these agents both in vitro and in vivo using both standard subcutaneous and stereotactic intracranial models.Since 2005,a large number of anti-glioma agents have been screened.Of those,25 new agents showed significant enough promise to warrant extended evaluation through the ABTC.These extended studies involved stereotactic-based intracranial models looking at various dose and administration schedules as well as combination trials of the new drug with other agents.Furthermore,ABTC provides experimental and technical support to other investigators both within and outside of the NOB for evaluating newly developed therapeutics.For example, the role of stem cell factor (SCF) in glioma angiogenesis; Notch-1 in glioma cell survival and proliferation;Stathmin in the resistance of malignant gliomas to DNA alkylating agents in vivo. Systemic as well as neurotoxicity (behavior) is also monitored by routine animal screening.In addition,a number of newer drug delivery technologies including intracarotid administration, delivery with or without selective or gross blood-brain barrier disruption, convection delivery, etc.have been evaluated in animal models within the ABTC.For example, the ABTC in collaboration with the SNB of NINDS and in collaboration with the private sector, has used convection-enhanced drug delivery (CED) to directly administer various genetic vectors into the brains of immundeficient animals harboring human glioma xenografts.Many of the new classes of anti-tumor therapeutics will have cytostatic rather than cytotoxic properties.Evaluating which of these agents will have biologic activity in humans in small,early clinical trials is a challenge since the standard response criteria are based on the determination of cytotoxic responses.The only truly valid clinical parameter available for evaluating the activity of a truly cytostatic agent is patient survival or tumor progression-free survival.These,however,are not useful parameters for screening drug activity in small,early phase clinical trials.Thus,if surrogate markers of biologic activity could be identified,one could utilize these as early endpoints for screening out agents with little or no clinical activity.Toward that end,the ABTC is actively working to develop surrogate markers of drug anti-tumor activity that can be utilized and validated in clinical trials,which includes three major areas:1)Imaging;2)Gene expression profiling;3) Proteinomics/Serum markers. For example, in collaboration with investigators in NOB, NINDS and the Clinical Centers program of experimental imaging science,noninvasive MR imaging has been used to image magnetically labeled endothelial progenitor cells in vivo to directly identify vasculogenesis in a glioma model.The core has provided the technical support for this project which involved the MRI tracking of in vivo Ferumoxides-Protamine Sulfate (FE-PRO) complex-labeled endothelial progenitor cells incorporating into the vasculature of established intracranial mouse gliomas.The ABTC has also successfully generated the preclinical toxicology data required by the FDA for preparation of our IND for the clinical trial of using ferrodex-labeled endothelial progenitor cells as MRI trackable markers of angiogenesis in patients with gliomas.Additionally,we have collaborated with Dr. Robert Innis(NIMH)for attempting to adapt PET scanning into a monitoring system for real time imaging of drug permeability through the BBB and following the administration of inhibitors of the multiple drug resistance (MDR) protein.This work is being extended to use the ABTC tohelp evaluate novel PET ligands that bind to the peripheral benzodiazepine receptors (PBR) which is highly overexpresed in gliomas.A major effort of the core is to generate the RNA for gene expression profiles using microarray technology from given glioma cell lines treated with a specific class of agents.If characteristic patterns could be identified that correspond with anti-tumor activity,then clinical trials can/will be devised to administer one of these agents to patients with brain tumors immediately prior to biopsy/surgery in order to attempt and identify a similar genetic profile clinically.In collaboration with the NOB Lab and the GMDI team,gene expression signatures are being generated in all of glioma cell lines and GIC/GSCs for all compounds tested within the ABTC.Finally,the ABTC stores representative tumor, tissue and serum samples from animals treated with each new compound tested with the expectations that new candidate tissue and/or serum-based protein markers of drug activity, tumor activity and/or some tumor biological process(i.e. angiogenesis)may be found.This will be an invaluable preclinical resource for validating such claims in the future.A major effort of the NOB is to develop human glioma cell lines that more closely model primary human gliomas both biologically and molecularly.The ABTC is actively involved in the generation of primary human glioma cell lines and GIC/GSC lines from fresh surgical specimens for every glioma patient operated on at the NIH.The ABTC staff works closely with the cancer stem cell biologists in the Fine laboratory for the growth, propagation and characterization of each of these cell lines and animal xenografts. The ABTC uses these well-characterized cell lines as screens for two major categories of drugs;1)The most promising of the drugs that have made it through the first levels of in vitro and in vivo screens using the more conventional established glioma cell lines;2)drugs that target pathways that may not be well represented by the biology of standard glioma cell lines but are reproduced in the GIC/GSCs.The cores expertise with these cells, and the large resources of different GIC/GSC lines, are a potent enticement for potential partnerships between NCI and the pharmaceutical/biotechnology community given their growing appreciation of the limitation of standard cancer cell lines and the promise of cancer stem cells for better representing the human disease.Finally, given the hundreds of requests we receive each year for these valuable GIC/GSC lines,the ABTC serves a vital function as the group designated to expand,freeze and distribute various cell lines to investigators both within and outside of the NIH.In doing so,the staff of the ABTC spends a significant amount of time teaching other investigators from within and outside of the NIH how to grow GIC/GSCs and how to perform stereotactic implantation of tumor cells into mice and rats.Evidence of the success of the ABTC is the fact that we have activated 11 clinical trials as a direct result of translational work performed within the NOB,all of which had preclinical animal studies performed within the ABTC.Even more to the point,we have identified 12 compounds solely through the ABTC preclinical screening program that have since been brought forward to clinical trials at the NIH (AZD6918,RO4929097,AZD8005,MLN-518, ZD6474,LY317615,sunitinib,CC5013,Talampanel).The potential power of the ABTC is well documented by our demonstration of being able to take an agent sent to us for preclinical evaluation by one of our pharmaceutical collaborators and generate preclinical data supportive of clinical trials that resulted in NOB sponsored (two) phase I trials,(two)phase II trials and a NOB-chaired phase III worldwide randomized registration clinical trial; all the while discovering a novel mechanism of action of the drug (GSK3 inhibition).

在Fine博士的领导下，NOB实验室与制药公司和学术机构合作，以及在临床前和临床开发的NCI发育治疗计划中，许多新的抗脱脂瘤代理商的第一步是通过ABTC筛选这些代理的开发管道的第一步。颅内模型。从2005年，已经筛选了大量抗脱脂瘤药物。对于这些药物，25个新代理人表现出足够的承诺，保证通过ABTC进行扩展评估。这些广泛的研究涉及基于立体的颅内模型，以进行各种剂量和给药的范围内，以及在各种剂量方面和其他技术培训和ABTC的组合试验。评估新开发的疗法的NOB。例如，干细胞因子（SCF）在神经胶质瘤血管生成中的作用；神经胶质瘤细胞存活和增殖中的Notch-1；在恶性神经胶质瘤对体内DNA烷基化剂的耐药性中。还可以通过常规动物筛查来监控系统性和神经毒性（行为）。此外，许多新的药物输送技术，包括果落内给药，有或没有选择性或没有选择性或严重的血脑屏障破坏，对流的递送，对流的递送等。对流增强的药物输送（CED）直接将各种遗传载体施加到具有人类神经胶质瘤异种移植的微不足道的动物的大脑中。新型抗肿瘤疗法的曼尼是细胞抑制剂具有细胞抑制性的，而不是细胞毒性的特性。细胞毒性反应。唯一可用于评估真正细胞抑制剂活性的真正有效的临床参数是患者的存活或肿瘤的无效生存。然而，这些不是在小型，早期临床试验中筛查药物活性的有用参数。这一目的，ABTC正在积极努力开发药物抗肿瘤活性的替代标记，这些标志物可以在临床试验中使用和验证，其中包括三个主要领域：1）成像； 2）基因表达分析； 3）蛋白质/血清标记物。例如，与NOB，NINDS和临床中心的研究人员合作，无创的MR成像已用于在体内形象图像磁性标记的内皮祖细胞，以直接识别胶质瘤模型中的血管生成。内皮祖细胞结合到已建立的颅内小鼠神经膜瘤的脉管系统中。ABTC还成功地生成了FDA为我们的IND准备IND所需的临床前毒理学数据，用于为使用Ferrodex-Label的临床试验，以使用Ferrodex-Labeled Endophial Endphialial Endphialial Endphiel-cromiartable Markers in MRI可跟踪的MRI可构成glibientation。 Innis(NIMH)for attempting to adapt PET scanning into a monitoring system for real time imaging of drug permeability through the BBB and following the administration of inhibitors of the multiple drug resistance (MDR) protein.This work is being extended to use the ABTC tohelp evaluate novel PET ligands that bind to the peripheral benzodiazepine receptors (PBR) which is highly overexpresed in神经膜瘤。核心的主要努力是使用给定的胶质瘤细胞系中的微阵列技术生成基因表达谱的RNA，这些细胞系用特定类别的药物处理。如果可以鉴定出与抗肿瘤活性相对应的特征模式，那么临床试验就可以/将在临床上进行临床特征，以与临床的临床疗法进行临床/术语，以与脑部的相似性进行，以固定术语，并进行术语，并进行临床的遗传性，并固定术语，并进行术语，并在同类中进行了术语，并进行了术语。 NOB实验室和GMDI团队，在所有在ABTC中测试的化合物的所有胶质瘤细胞系和GIC/GSC中都会产生基因表达特征。从本文中，ABTC储存了代表性的肿瘤，组织和血清样品，由每种新的新型化合物处理的动物与某些新型候选活动和或或或抑制了某些候选性的组织/或或或或抑制了药物的活性蛋白蛋白和/tumor的蛋白质蛋白质蛋白质蛋白质蛋白质和/tumor的蛋白酶蛋白酶，并将其分析。过程（即。可能会发现血管生成）。这将是一个无价的临床前资源，用于验证此类主张，在将来验证此类主张。 ABTC的工作人员与癌症干细胞生物学家在精细实验室中紧密合作，以生长，传播和表征这些细胞系和动物异种移植物。 ABTC使用这些良好特征的细胞系作为两种主要类别的药物的筛选； 1）最有前途的药物是通过使用更常规的胶质瘤细胞系中的第一个体外和体内筛选来实现的药物； 2）靶向可能无法很好地代表这些途径的药物，这些途径可能是由这些细胞构成的，这些途径均由这些标准的Glioma Cell lines and repod and/repods repods repod and/repod secred and/repod ode repod and/repod seprod and/reod gccection and gcic and gcics。 resources of different GIC/GSC lines, are a potent enticement for potential partnerships between NCI and the pharmaceutical/biotechnology community given their growing appreciation of the limitation of standard cancer cell lines and the promise of cancer stem cells for better representing the human disease.Finally, given the hundreds of requests we receive each year for these valuable GIC/GSC lines,the ABTC serves a vital function as the group designated to expand,freeze and distribute在NIH内外，各种细胞线。这样做，ABTC的工作人员花费大量时间从NIH内外教其他研究人员如何发展GIC/GSC，以及如何执行肿瘤细胞的立体定位植入到鼠标中的态度和大比例，所有的abtc的事实是，我们在我们的ABTC成功中表现出了一定的责任，这是我们在启用了一项著作。在ABTC中进行的临床前动物研究。甚至更多，我们仅通过ABTC临床前筛查计划确定了12种化合物，此后已通过NIH进行了临床试验（AZD6918，RO4929097 ZD6474,LY317615,sunitinib,CC5013,Talampanel).The potential power of the ABTC is well documented by our demonstration of being able to take an agent sent to us for preclinical evaluation by one of our pharmaceutical collaborators and generate preclinical data supportive of clinical trials that resulted in NOB sponsored (two) phase I trials,(two)phase II trials and a NOB主持的III期全球随机注册临床试验；一直发现药物的新型作用机理（GSK3抑制）。