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发展治疗项目合作，进行了许多新型抗胶质瘤药物的临床前和临床开发。开发管道的第一步是通过ABTC筛选代理。ABTC提供专业的服务，在体外和体内筛选这些药物，使用标准的皮下和立体定向颅内模型。自2005年以来，大量抗胶质瘤药物被筛选出来。其中，25种新药显示出足够的前景，值得通过ABTC进行延长评估。这些扩展的研究包括基于立体定向的颅内模型，观察各种剂量和给药计划，以及新药与其他药物的联合试验。此外，ABTC还提供给药时间表以及新药与其他药物的联合试验。此外，ABTC为NOB内外的其他研究人员提供实验和技术支持，以评估新开发的治疗方法。例如，干细胞因子（SCF）在胶质瘤血管生成中的作用；Notch-1在胶质瘤细胞存活和增殖中的作用安定素在恶性胶质瘤对DNA烷基化剂体内抵抗中的作用。该核心已经产生了基因表达谱的RNA，使用微阵列技术从给定的胶质瘤细胞系与特定类别的药物处理。一旦确定了与抗肿瘤活性相对应的特征模式，那么就可以/将设计临床试验，在活检/手术之前立即将这些药物中的一种施用于脑肿瘤患者，以便尝试在临床上确定类似的基因谱。在与NOB实验室和Genomic Core团队的合作下，在ABTC内测试的所有化合物的所有胶质瘤细胞系和GIC/GSCs中产生了基因表达特征。此外，一些较新的给药技术，包括颈动脉内给药、有或没有选择性或总体血脑屏障破坏的给药、对流给药等，已经在ABTC的动物模型中进行了评估。许多新型的抗肿瘤治疗药物将具有细胞抑制而不是细胞毒性。由于标准反应标准是基于细胞毒性反应的确定，因此在小型早期临床试验中评估这些药物中哪些在人体中具有生物活性是一项挑战。评估真正的细胞抑制剂活性的唯一真正有效的临床参数是患者生存期或肿瘤无进展生存期。然而，这些并不是筛选小型早期临床试验药物活性的有用参数。因此，如果生物活性的替代标记物可以被识别，人们可以利用这些作为筛选很少或没有临床活性的药物的早期终点。为此，ABTC正积极致力于开发可用于临床试验的药物抗肿瘤活性替代标志物，其中包括三个主要领域：1)成像；2)基因表达谱；3)蛋白质组学/血清标志物。例如，在与NOB、NINDS和临床中心实验成像科学项目的研究人员的合作中，无创磁共振成像已被用于对体内磁性标记的内皮祖细胞进行成像，以直接识别胶质瘤模型中的血管发生。最后，ABTC储存了用每种新化合物处理过的动物的代表性肿瘤、组织和血清样本，以期发现新的候选组织和/或基于血清的药物活性、肿瘤活性和/或某些肿瘤生物过程（即血管生成）的蛋白质标志物。这将是未来验证此类声明的宝贵临床前资源。NOB的一项主要工作是开发人类胶质瘤细胞系，使其在生物学和分子上更接近于模拟原发性人类胶质瘤。ABTC积极参与从NIH手术的每个胶质瘤患者的新鲜手术标本中产生原发性人类胶质瘤细胞系和GIC/GSC细胞系。ABTC工作人员与癌症干细胞生物学家密切合作，对每种细胞系和动物异种移植物进行生长、繁殖和表征。ABTC使用这些特性良好的细胞系作为两大类药物的筛选；1)利用更传统的已建立的胶质瘤细胞系，从体外和体内筛选的第一阶段中获得最有希望的药物；2)针对标准胶质瘤细胞系生物学不能很好地代表但在GIC/GSCs中复制的途径的药物。这些细胞的实验室专业知识，以及不同GIC/GSC系的大量资源，是NCI与制药/生物技术界之间潜在合作伙伴关系的强大吸引力，因为他们越来越认识到标准癌细胞系的局限性，以及癌症干细胞更好地代表人类疾病的前景。ABTC成功的证据是，我们已经启动了11项临床试验，这是NOB内进行的转化工作的直接结果，所有这些临床试验都在ABTC内进行了临床前动物研究。更重要的是，我们已经通过ABTC临床前筛选项目鉴定了12种化合物，这些化合物已经在NIH进行了临床试验（AZD6918, RO4929097, AXD8005, MLN-518, ZD6474, LY317615, Sunitinib, CC5013, Talampanel）。在Gilbert博士的新领导下，ABTC正在扩展转化研究，如实验性免疫治疗和代谢靶向治疗。