ZIC BC 011086 (ZIC) | |||
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Title | Brain Tumor Animal Therapeutics Core | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Gress, Ronald | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $330,398 | Project Dates | 10/01/2007 - 00/00/0000 |
Fiscal Year | 2014 | 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 | |||
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 eval" |