Pre-clinical Translational Research Facility

临床前转化研究设施

• 批准号: 9556860
• 负责人: Mark Gilbert
• 金额: $ 172.99万
• 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/9556860
• 关键词: Animal Experiments; Animal Model; Animals; Area; Biological; Biological Markers; Biological Process; Biology; Biopsy; Biotechnology; Blood - brain barrier anatomy; Brain Neoplasms; Brain Stem Neoplasms; Breeding; Cancer cell line; Categories; Cell Line; Cells; Central Nervous System Neoplasms; Characteristics; Clinic; Clinical; Clinical Drug Development; Clinical Investigator; Clinical Trials; Clinical Trials Design; Collaborations; Communities; Convection; Cytostatics; Data; Development; Developmental Therapeutics Program; Diagnostic; Dose; Drug Delivery Systems; Drug Targeting; Evaluation; Extramural Activities; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Generations; Genetic; Genomics; Glioma; Growth; Human; Image; Immunotherapeutic agent; In Vitro; Institution; Investigational Therapies; Label; Laboratories; Magnetic Resonance Imaging; Magnetism; Metabolic; Methods; Mission; Modeling; Molecular; Molecular Profiling; National Institute of Neurological Disorders and Stroke; Operative Surgical Procedures; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Preclinical Drug Evaluation; Program Development; Progression-Free Survivals; Property; Protective Agents; RNA; Radiation-Sensitizing Agents; Research; Research Design; Research Personnel; Resources; Sampling; Schedule; Science; Serum; Serum Markers; Services; Specimen; Stem cells; Surrogate Markers; Technology; Testing; Therapeutic; Tissues; Translational Research; Tumor Cell Line; Tumor Tissue; United States National Institutes of Health; Work; Xenograft procedure; activity marker; angiogenesis; antitumor agent; antitumor drug; base; cancer stem cell; clinical development; cytotoxic; design; expectation; experimental study; genetic profiling; glioma cell line; human disease; in vivo; mouse model; novel; novel therapeutics; pre-clinical; preclinical development; programs; protein biomarkers; relating to nervous system; repository; research facility; response; screening; subcutaneous; targeted treatment; translational study; tumor; tumor progression; vasculogenesis

The major mission of the PTRF is to provide services for clinical investigators to evaluate potential new anti glioma agents in vitro and in vivo. 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 PTRF that provides the professional service for screening these agents both in vitro and in vivo using both standard subcutaneous and stereotactic intracranial models. Furthermore, PTRF provides experimental and technical support to other investigators both within and outside of the NOB for evaluating newly developed therapeutics. 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. For example, the PTRF has helped to generate the RNA for gene expression profiles for 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 PTRF. 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 PTRF. 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 PTRF 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 PTRF 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 PTRF is actively involved in the generation of primary human glioma cell lines and GIC/GSC lines from fresh surgical specimens for glioma patient operated on at the NIH. Working closely with the cancer stem cell biologists for the growth, propagation and characterization of each of these cell lines and animal xenografts, the PTRF 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) The 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 utilizing 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. Since the PTRF was initiated in 2016, four clinical trials have activated as a direct result of translational work performed within the NOB, all of which had preclinical animal studies performed within the facility. Furthermore, we have identified 3 compounds solely through the preclinical screening program that have since been brought forward to clinical trials at the NIH (Regadenoson, TG02, LB100). PTRF is further extending the translational studies, such as experimental immunotherapeutics and metabolic targeting therapeutics, as well as the experimental therapeutics for rare CNS tumors (Animal Study Proposal: NOB005, 006, and 008).

PTRF的主要任务是为临床研究人员提供服务，以评估潜在的体外和体内抗胶质瘤新药。Nob实验室与制药公司和学术机构以及NCI开发治疗计划合作，开发了许多新的抗胶质瘤药物。开发流程的第一步是通过PTRF筛选药物，PTRF提供专业服务，使用标准的皮下和立体定向颅内模型在体外和体内筛选这些药物。此外，PTRF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。这些扩展的研究包括基于立体定向的颅内模型，观察不同的剂量和给药时间表，以及新药与其他药物的联合试验。例如，PTRF已经帮助生成了特定类别药物处理的特定胶质瘤细胞系的基因表达谱的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，在活组织检查/手术之前立即给脑肿瘤患者使用这些药物中的一种，以尝试并在临床上确定类似的基因图谱。在与NOB实验室和基因组核心团队的合作下，正在为所有胶质瘤细胞系和在PTRF内测试的所有化合物的GIC/GSC生成基因表达签名。此外，许多较新的给药技术，包括颈动脉内给药，选择性或不选择性血脑屏障破坏的给药，对流给药等，已经在PTRF内的动物模型中进行了评估。许多新的抗肿瘤治疗药物将具有细胞抑制而不是细胞毒性特性。在早期的小型临床试验中，评估这些药物中的哪一种将在人类身上具有生物活性是一项挑战，因为标准反应标准是基于细胞毒性反应的确定。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，在小型早期临床试验中，这些并不是筛选药物活性的有用参数。因此，如果能够确定生物活性的替代标记物，就可以利用这些标记物作为早期终点来筛选出临床活性很低或没有临床活性的药物。为此，PTRF正在积极开发可在临床试验中使用和验证的药物抗肿瘤活性的替代标记物，包括三个主要领域：1)成像；2)基因表达谱；3)蛋白质组学/血清标记物。例如，与NOB、NINDS和临床中心实验成像科学计划的研究人员合作，非侵入性磁共振成像已被用于在体内成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。最后，PTRF存储用每一种新化合物治疗的动物的代表性肿瘤、组织和血清样本，预期可能会发现新的候选组织和/或基于血清的蛋白质标记物，反映药物活性、肿瘤活性和/或某些肿瘤生物学过程(即血管生成)。这将是一个无价的临床前资源，用于在未来验证这种说法。NOB的一个主要努力是发展人类胶质瘤细胞系，在生物学和分子上更接近于模拟原发人类胶质瘤。PTRF积极参与从NIH手术的胶质瘤患者的新鲜手术标本中产生原代人类胶质瘤细胞系和GIC/GSC系。PTRF与癌症干细胞生物学家密切合作，研究这些细胞系和动物异种移植的生长、繁殖和特性，将这些特性良好的细胞系用作两大类药物的筛选：1)来自一级的最有希望的体外和体内药物筛选使用更传统的已建立的胶质瘤细胞系；2)靶向那些可能不能很好地代表标准胶质瘤细胞系的生物学但在GIC/GSC中复制的通路的药物。利用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和制药/生物技术社区之间潜在合作伙伴关系的强大诱惑力，因为他们越来越认识到标准癌症细胞系的局限性，以及癌症干细胞更好地代表人类疾病的前景。自2016年PTRF启动以来，已启动四项临床试验，这是在NOB内进行的翻译工作的直接结果，所有这些试验都在该设施内进行了临床前动物研究。此外，我们仅通过临床前筛选程序确定了3种化合物，自那以后已在NIH进行临床试验(regadoson，TG02，LB100)。PTRF正在进一步扩大翻译研究，如实验性免疫疗法和代谢靶向疗法，以及罕见中枢神经系统肿瘤的实验疗法(动物研究建议：NOB005、006和008)。