Pre-clinical Translational Research Facility

临床前转化研究设施

• 批准号: 10926645
• 负责人: Mark Gilbert
• 金额: $ 238.68万
• 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/10926645
• 关键词: Animal Experiments; Animal Model; Animals; Area; Biological; Biological Markers; Biological Process; Biology; Biopsy; Biotechnology; Brain Neoplasms; Breeding; Camptothecin-11; 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; Cooperative Research and Development Agreement; Cytostatics; Data; Development; Developmental Therapeutics Program; Diagnostic; Dose; Drug Delivery Systems; Drug Screening; 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; Intracarotid; Investigational Therapies; Label; Laboratories; Magnetic Resonance Imaging; Magnetism; Metabolic; Methods; Mission; Modeling; Molecular; Mus; National Institute of Neurological Disorders and Stroke; Operative Surgical Procedures; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Program Development; Progression-Free Survivals; Property; Protective Agents; RNA; Radiation-Sensitizing Agents; Reagent; Research; Research Design; Research Personnel; Resources; SN-38; Sampling; Schedule; Serum; Serum Markers; Services; Specimen; Surrogate Markers; Technology; Testing; Therapeutic; Tissues; Translational Research; Tumor Cell Line; Tumor Stem Cells; United States National Institutes of Health; Work; Xenograft procedure; angiogenesis; antitumor agent; antitumor drug; blood-brain barrier disruption; cancer stem cell; clinical center; clinical development; cytotoxic; design; early phase clinical trial; endothelial stem cell; expectation; experimental study; glioma cell line; human disease; imaging science; in vivo; irinotecan; mouse model; neural; novel; novel therapeutics; pre-clinical; precision medicine; preclinical development; programs; protein biomarkers; repository; research facility; response; screening; screening program; stem cell biology; stem cells; 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 (described above in the project Exploring the Therapeutic Potential of Stem Cell Biology in Gliomas) 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 PTRF 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). One reagent Irinotecan (CPT-11/SN-38) has also been tested on mouse glioma xenografts recently. PTRF is further extending the translational studies, such as experimental immunotherapeutics, synthetic lethality for the Precision Medicine Program and metabolic targeting therapeutics, as well as the experimental therapeutics for rare CNS tumors PTRF is further extending the translational studies, such as experimental immunotherapeutics, synthetic lethality for the Precision Medicine Program and metabolic targeting therapeutics, as well as the experimental therapeutics for rare CNS tumors (Animal Study Proposal: NOB001, 005, 007, 008, 021, 023, and 024).

PTRF的主要使命是为临床研究人员提供服务，以评估潜在的新的抗胶质瘤药物在体外和体内。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，在临床前和临床上开发了许多新的抗胶质瘤药物。开发管道的第一步是通过PTRF筛选药物，PTRF提供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的专业服务。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。这些扩展研究涉及基于立体定向的颅内模型，研究各种剂量和给药方案以及新药与其他药物的联合试验。例如，PTRF已经帮助生成用特定类别的药剂处理的给定神经胶质瘤细胞系的基因表达谱的RNA。一旦识别出与抗肿瘤活性相对应的特征模式，那么可以/将设计临床试验，在活检/手术前立即向脑肿瘤患者施用其中一种药物，以尝试并在临床上识别类似的遗传特征。与NOB实验室和基因组核心团队合作，正在PTRF内测试的所有化合物的所有胶质瘤细胞系和GIC/GSC中生成基因表达特征。此外，已经在PTRF内的动物模型中评价了许多较新的药物递送技术，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递送、对流递送等。许多新型抗肿瘤治疗剂将具有细胞抑制而非细胞毒性特性。在小型早期临床试验中评价这些药物中哪一种将在人体中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测定。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期或肿瘤无进展生存期。然而，这些在小规模的早期临床试验中并不是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志物，则可以利用这些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，PTRF正在积极努力开发可用于临床试验和验证的药物抗肿瘤活性的替代标志物，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，与NOB、NINDS和实验成像科学临床中心项目的研究人员合作，非侵入性MR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，PTRF存储了来自用每种新化合物治疗的动物的代表性肿瘤、组织和血清样品，期望可以发现药物活性、肿瘤活性和/或一些肿瘤生物学过程（即血管生成）的新候选组织和/或基于血清的蛋白质标志物，这将是未来验证此类声明的宝贵临床前资源。NOB的一个主要努力是开发人类神经胶质瘤细胞系，在生物学和分子学上更接近原发性人类神经胶质瘤的模型。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物的生长、繁殖和特征，（在上面的项目“探索神经胶质瘤中干细胞生物学的治疗潜力”中描述）作为两大类药物的筛选; 1）使用更常规的已建立的胶质瘤细胞系，从体外和体内筛选的第一级筛选最有希望的药物; 2）靶向标准胶质瘤细胞系的生物学可能不能很好地代表但在GIC/GSC中再现的途径的药物。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/生物技术界之间潜在合作伙伴关系的有力诱惑，因为他们越来越认识到标准癌细胞系的局限性和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，NOB内开展的翻译工作直接导致了四项临床试验的启动，所有这些试验都在该机构内进行了临床前动物研究。此外，我们仅通过临床前筛选计划确定了3种化合物，这些化合物已在NIH进行临床试验（Regadenoson，TG 02，LB 100）。最近还对一种试剂伊立替康（CPT-11/SN-38）在小鼠胶质瘤异种移植物中进行了测试。PTRF正在进一步扩展转化研究，如实验免疫治疗，精准医学计划的合成致死性和代谢靶向治疗，以及罕见CNS肿瘤的实验治疗PTRF正在进一步扩展转化研究，如实验免疫治疗，精准医学计划的合成致死性和代谢靶向治疗，以及用于罕见CNS肿瘤的实验治疗（动物研究提案：NOB 001、005、007、008、021、023和024）。

项目成果

Quantitation of the next-generation imipridone ONC206 in human plasma by a simple and sensitive UPLC-MS/MS assay for clinical pharmacokinetic application.

• DOI: 10.1016/j.jpba.2022.114685
• 发表时间: 2022-05-10
• 期刊: Journal of pharmaceutical and biomedical analysis
• 影响因子: 3.4
• 作者: Goodell JC;Zimmerman SM;Peer CJ;Prabhu V;Yin T;Richardson WJ;Azinfar A;Dunn JA;Mullin M;Theeler BJ;Gilbert M;Figg WD
• 通讯作者: Figg WD

Detection of Metabolic Changes Induced via Drug Treatments in Live Cancer Cells and Tissue Using Raman Imaging Microscopy.

使用拉曼成像显微镜检测活癌细胞和组织中药物治疗引起的代谢变化。

• DOI: 10.3390/bios9010005
• 发表时间: 2018
• 期刊: Biosensors
• 作者: Larion,Mioara;Dowdy,Tyrone;Ruiz-Rodado,Victor;Meyer,MatthewW;Song,Hua;Zhang,Wei;Davis,Dionne;Gilbert,MarkR;Lita,Adrian
• 通讯作者: Lita,Adrian

Adenosine A2A Receptor Activation Enhances Blood-Tumor Barrier Permeability in a Rodent Glioma Model.

• DOI: 10.1158/1541-7786.mcr-19-0995
• 发表时间: 2021-12
• 期刊: Molecular cancer research : MCR
• 作者: Vézina A;Manglani M;Morris D;Foster B;McCord M;Song H;Zhang M;Davis D;Zhang W;Bills J;Nagashima K;Shankarappa P;Kindrick J;Walbridge S;Peer CJ;Figg WD;Gilbert MR;McGavern DB;Muldoon LL;Jackson S
• 通讯作者: Jackson S

Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy.

• DOI: 10.1186/s40425-018-0371-5
• 发表时间: 2018-06-11
• 期刊: Journal for immunotherapy of cancer
• 影响因子: 10.9
• 作者: Giles AJ;Hutchinson MND;Sonnemann HM;Jung J;Fecci PE;Ratnam NM;Zhang W;Song H;Bailey R;Davis D;Reid CM;Park DM;Gilbert MR
• 通讯作者: Gilbert MR