Under the leadership of Dr Fine,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 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. Systemic as well as neurotoxicity (behavior) is also monitored by routine animal screening.In addition,a number of newer drug delivery technologies including intracarotid administration, delivery with or without selective or gross blood-brain barrier disruption, convection delivery, etc.have been evaluated in animal models within the ABTC.For example, the ABTC in collaboration with the SNB of NINDS and in collaboration with the private sector, has used convection-enhanced drug delivery (CED) to directly administer various genetic vectors into the brains of immundeficient animals harboring human glioma xenografts.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 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.The core has provided the technical support for this project which involved the MRI tracking of in vivo Ferumoxides-Protamine Sulfate (FE-PRO) complex-labeled endothelial progenitor cells incorporating into the vasculature of established intracranial mouse gliomas.The ABTC has also successfully generated the preclinical toxicology data required by the FDA for preparation of our IND for the clinical trial of using ferrodex-labeled endothelial progenitor cells as MRI trackable markers of angiogenesis in patients with gliomas.Additionally,we have collaborated with Dr. Robert Innis(NIMH)for attempting to adapt PET scanning into a monitoring system for real time imaging of drug permeability through the BBB and following the administration of inhibitors of the multiple drug resistance (MDR) protein.This work is being extended to use the ABTC to help evaluate novel PET ligands that bind to the peripheral benzodiazepine receptors (PBR) which is highly overexpresed in gliomas.A major effort of the core is to generate the RNA for gene expression profiles using microarray technology from given glioma cell lines treated with a specific class of agents.If characteristic patterns could be 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 GMDI team,gene expression signatures are being generated in all of glioma cell lines and GIC/GSCs for all compounds tested within the ABTC.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 in the Fine laboratory 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 of the drugs that have made it through 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 cores 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.Finally, given the hundreds of requests we receive each year for these valuable GIC/GSC lines,the ABTC serves a vital function as the group designated to expand,freeze and distribute various cell lines to investigators both within and outside of the NIH.In doing so,the staff of the ABTC spends a significant amount of time teaching other investigators from within and outside of the NIH how to grow GIC/GSCs and how to perform stereotactic implantation of tumor cells into mice and rats.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,AZD8005,MLN-518, ZD6474,LY317615,sunitinib,CC5013,Talampanel).The potential power of the ABTC is well documented by our demonstration of being able to take an agent sent to us for preclinical evaluation by one of our pharmaceutical collaborators and generate preclinical data supportive of clinical trials that resulted in NOB sponsored (two) phase I trials,(two)phase II trials and a NOB-chaired phase III worldwide randomized registration clinical trial;all the while discovering a novel mechanism of action of the drug (GSK3 inhibition).
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| Li, Aiguo; Bozdag, Serdar; Kotliarov, Yuri et al. (2010) GliomaPredict: a clinically useful tool for assigning glioma patients to specific molecular subtypes. BMC Med Inform Decis Mak 10:38 |
