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、学术机构以及NCI开发治疗计划合作，进行多种新型抗神经胶质瘤药物的临床前和临床开发。开发流程的第一步是通过 ABTC 筛选代理。 ABTC 提供专业服务，使用标准皮下和立体定向颅内模型在体外和体内筛选这些药物。自2005年以来，大量抗神经胶质瘤药物被筛选出来。其中，25 名新代理商表现出足够大的前景，值得通过 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，着眼于各种剂量和给药方案以及新药与其他药物的联合试验。此外，ABTC 还提供给药方案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，以评估新开发的疗法。例如，干细胞因子（SCF）在神经胶质瘤血管生成中的作用； Notch-1 在神经胶质瘤细胞存活和增殖中的作用； Stathmin在体内恶性胶质瘤对DNA烷化剂的抵抗中的作用。核心使用微阵列技术从用特定类别药物处理的给定神经胶质瘤细胞系中生成基因表达谱的 RNA。一旦确定了与抗肿瘤活性相对应的特征模式，就可以/将设计临床试验，在活检/手术前立即向患有脑肿瘤的患者施用这些药物中的一种，以尝试并在临床上确定类似的遗传谱。与 NOB 实验室和基因组核心团队合作，正在所有神经胶质瘤细胞系和 GIC/GSC 中生成 ABTC 中测试的所有化合物的基因表达特征。此外，许多较新的药物输送技术，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输送、对流输送等，已经在 ABTC 的动物模型中进行了评估。许多新型抗肿瘤疗法将具有细胞抑制特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哪些在人体中具有生物活性是一个挑战，因为标准反应标准是基于细胞毒性反应的确定。可用于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，如果可以鉴定生物活性的替代标记，人们就可以利用它们作为筛选具有很少或没有临床活性的药物的早期终点。为此，ABTC 正在积极致力于开发可在临床试验中使用和验证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项目的研究人员合作，无创 MR 成像已用于对体内磁性标记的内皮祖细胞进行成像，以直接识别神经胶质瘤模型中的血管生成。最后，ABTC 存储来自用每种新化合物治疗的动物的代表性肿瘤、组织和血清样本，并期望药物活性、肿瘤活性和/或某些肿瘤生物学过程（即，新的候选组织和/或基于血清的蛋白质标记）。血管生成）可能会被发现。这将是未来验证此类主张的宝贵临床前资源。 NOB 的一项主要工作是开发人类神经胶质瘤细胞系，在生物学和分子方面更接近地模拟原发性人类神经胶质瘤。 ABTC 积极参与从 NIH 接受手术的每位神经胶质瘤患者的新鲜手术标本中生成原代人类神经胶质瘤细胞系和 GIC/GSC 细胞系。 ABTC 工作人员与癌症干细胞生物学家密切合作，研究每种细胞系和动物异种移植物的生长、繁殖和表征。 ABTC 使用这些特征明确的细胞系作为两大类药物的筛选； 1）使用更常规的已建立的神经胶质瘤细胞系进行第一级体外和体内筛选最有前途的药物； 2）针对标准神经胶质瘤细胞系的生物学特性可能无法很好地代表但在 GIC/GSC 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，对于 NCI 和制药/生物技术界之间的潜在合作伙伴关系具有强大的吸引力，因为他们越来越认识到标准癌细胞系的局限性和癌症的前景干细胞可以更好地代表人类疾病。 ABTC 成功的证据是，我们启动了 11 项临床试验，作为 NOB 内进行的转化工作的直接结果，所有这些试验都在 ABTC 内进行了临床前动物研究。更重要的是，我们仅通过 ABTC 临床前筛选计划就鉴定出了 12 种化合物，这些化合物已被提交至 NIH 进行临床试验（AZD6918、RO4929097、AXD8005、MLN-518、ZD6474、LY317615、Sunitinib、CC5013、Talampanel） ）。在 Gilbert 博士的新领导下，ABTC 正在扩展实验性免疫治疗和代谢靶向治疗等转化研究。