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.
| Giles, Amber J; Hutchinson, Marsha-Kay N D; Sonnemann, Heather M et al. (2018) Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy. J Immunother Cancer 6:51 |
| Su, Yu-Ting; Chen, Robert; Wang, Herui et al. (2018) Novel Targeting of Transcription and Metabolism in Glioblastoma. Clin Cancer Res 24:1124-1137 |
