ZIC BC 011641 (ZIC) | |||
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Title | Pre-clinical Translational Research Facility | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Gilbert, Mark | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $1,395,088 | Project Dates | null - null |
Fiscal Year | 2018 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) |
Brain (100.0%) Nervous System (100.0%) |
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Research Type | |||
Localized Therapies - Discovery and Development Systemic Therapies - Discovery and Development |
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Abstract | |||
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 parameters available for evaluating the activity of a truly cytostatic agent are 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 e |