Brain Tumor Animal Therapeutics Core (Scientific Cores)

脑肿瘤动物治疗核心（科学核心）

• 批准号: 9154353
• 负责人: Mark Gilbert
• 金额: $ 55.66万
• 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/9154353
• 关键词: Alkylating Agents; Animal Experiments; Animal Model; Animals; Area; Biological; Biological Process; Biology; Biopsy; Biotechnology; Blood - brain barrier anatomy; 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; Convection; Cytostatics; DNA; Data; Development; Developmental Therapeutics Program; Diagnostic; Dose; Drug Delivery Systems; Drug Targeting; Evaluation; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Generations; Genetic; Genomics; Glioma; Growth; Human; Image; Immunotherapeutic agent; In Vitro; Institution; LY317615; Label; Laboratories; Leadership; Magnetic Resonance Imaging; Malignant Glioma; Metabolic; Methods; Microarray Analysis; Mission; Modeling; Molecular Profiling; National Institute of Neurological Disorders and Stroke; New Agents; Operative Surgical Procedures; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Preclinical Drug Evaluation; Progression-Free Survivals; Property; Protective Agents; Proteins; RNA; Radiation-Sensitizing Agents; 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; Tissues; 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; genetic profiling; glioma cell line; human disease; in vivo; mouse model; neuro-oncology; notch protein; novel; pre-clinical; programs; relating to nervous system; repository; research study; response; screening; stathmin; subcutaneous; success; therapeutic target; translational study; tumor; tumor progression; vasculogenesis

Since established in 2004, 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 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. The core has generated the RNA for gene expression profiles using microarray technology from given glioma cell lines treated with a specific class of agents. Once characteristic patterns are 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 Genomic Core team, gene expression signatures are being generated in all of glioma cell lines and GIC/GSCs for all compounds tested within the ABTC. In addition, a number of newer drug delivery technologies including intra-carotid administration, delivery with or without selective or gross blood-brain barrier disruption, convection delivery, etc. have been evaluated in animal models within the ABTC. 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 are 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. 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 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 drugs from 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 laboratory 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. 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, AXD8005, MLN-518, ZD6474, LY317615, Sunitinib, CC5013, Talampanel). Under the new leadership of Dr. Gilbert, ABTC is extending the translational studies, such as experimental immunotherapeutics and metabolic targeting therapeutics.

自2004年成立以来，NOB实验室与制药公司和学术机构以及NCI发育疗法计划合作，用于临床前和临床开发的许多新的抗激瘤药物。开发管道的第一步是通过ABTC筛选代理。 ABTC提供了使用标准皮下和立体定向性颅内模型在体外和体内筛查这些药物的专业服务。自2005年以来，已经筛选了大量抗激瘤药物。其中，有25位新代理人表现出足够的承诺，可以通过ABTC进行扩展评估。这些扩展研究涉及基于立体定向的颅内模型，以研究各种剂量和给药时间表以及新药与其他药物的组合试验。此外，ABTC与其他药物一起提供了新药的管理时间表以及新药的组合试验。此外，ABTC为NOB内外的其他研究人员提供了实验和技术支持，以评估新开发的疗法。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；恶性神经胶质瘤对体内DNA烷基化剂的耐药性。核心使用特定类型剂处理的给定神经胶质瘤细胞系中的微阵列技术生成了基因表达谱的RNA。一旦确定了与抗肿瘤活性相对应的特征模式，则可以/将设计临床试验，以/将在活检/手术前立即向脑瘤患者施用其中一种，以便在临床上尝试和识别类似的遗传概况。与NOB实验室和基因组核心团队合作，用于在ABTC中测试的所有化合物中，在所有神经胶质瘤细胞系和GIC/GSC中都会生成基因表达特征。此外，已经在ABTC的动物模型中评估了许多较新的药物输送技术，包括 - 偶然内部给药，具有或不具有选择性或粗脑屏障破坏，对流递送等，对流的递送，对流递送等。许多新类别的抗肿瘤疗法将具有细胞抑制性而不是细胞毒性特性。在小型早期临床试验中，评估这些药物中的哪些药物将在人类中具有生物活性，这是一个挑战，因为标准响应标准基于细胞毒性反应的确定。可用于评估真正细胞抑制剂活性的唯一真正有效的临床参数是患者生存或无肿瘤进展生存。但是，这些不是在小型早期临床试验中筛选药物活性的有用参数。因此，如果可以确定生物活性的替代标记物，则可以将其用作早期终点，以筛选出很少或没有临床活性的药物。为此，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）蛋白质组学/血清标记。例如，与NOB，NINDS和实验成像科学临床中心计划的研究人员合作，无创的MR成像已用于在体内对磁性标记的内皮祖细胞进行图像，以直接识别胶质瘤模型中的血管生成。最后，ABTC存储了来自每种新化合物的动物的代表性肿瘤，组织和血清样品，并希望发现新候选组织和/或基于血清的药物活性，肿瘤活性和/或某些肿瘤生物学过程（即血管生成）的预期。这将是将来验证此类索赔的宝贵临床前资源。 NOB的主要努力是开发人神经胶质瘤细胞系，这些细胞系在生物学和分子上更加紧密地对原代人神经胶质瘤进行了模拟。 ABTC积极参与来自新鲜手术标本的原发性人神经胶质瘤细胞系和GIC/GSC系的生成，用于在NIH上进行的每个神经胶质瘤患者。 ABTC的工作人员与癌症干细胞生物学家紧密合作，以生长，传播和表征这些细胞系和动物异种移植物。 ABTC使用这些良好的细胞系作为两种主要类别的药物的筛选。 1）使用更常规的胶质瘤细胞系中最初的体外和体内筛查水平的最有前途的药物； 2）靶向可能无法很好地代表标准神经胶质瘤细胞系但在GIC/GSC中再现的药物。这些细胞的实验室专业知识以及不同的GIC/GSC线的大量资源是对NCI与药物/生物技术社区之间潜在伙伴关系的有力诱惑，因为它们对标准癌细胞系的限制以及癌症干细胞的限制越来越多，可以更好地代表人类疾病。 ABTC成功的证据是，我们已经激活了11项临床试验，这是NOB中进行的翻译工作的直接结果，所有这些都在ABTC中进行了临床前动物研究。 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, AXD8005, MLN-518, ZD6474, LY317615, Sunitinib, CC5013, Talampanel).在吉尔伯特博士的新领导下，ABTC正在扩展转化研究，例如实验性免疫治疗和代谢靶向治疗。