Crenolanib in Vitro Therapy in a RCAS/tv-a Murine Model of Di use Pontine Brainstem GliomaKeywords: astrocytoma, animal model, brain stem, glioma, chemotherapyInteractive Manuscript
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What is the background behind your study?
This recapitulates the genetic alteration of 30-40% of DIPGs, which harbor amplification of PDGFR-a. Despite clinical trials using chemotherapy, novel targeted agents, and radiation, the natural history of this disease has not been significantly affected and 90% of children with DIPGs die within 2 years of diagnosis.
What is the purpose of your study?
A first phase preclinical study was performed in a genetically engineered mouse model of Diffuse Intrinsic Pontine Glioma (DIPG). This model is driven by over-expression of PDGF-B ligand in nestin expressing cells in the brainstem of Ink4a-ARF deficient mice using the RCAS/tv-a gene transfer system.
Describe your patient group.
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Describe what you did.
BSG cells were harvested from the BSG model and treated in vitro. BrdU and MTT assays were completed to evaluate the anti-tumor activity of a small molecule inhibitor of PDGFR-a (Crenolanib) alone and in combination with rapamycin relative to vehicle-treated cells.
Describe your main findings.
BrdU assays in vitro revealed the IC50 of Crenolanib to be 10nM in the PDGF-B-driven BSG tumor cells; the IC50 by MTT assays was 1.25µM. The IC50 of rapamycin by BrdU was 1 µM; when 10 nM Crenolanib and 1 µM rapamycin were combined and evaluated by BrdU assay, the inhibition of proliferation relative to vehicle-treated cells was greater than 90%.
Describe the main limitation of this study.
This study used a specific model that may not translate to humans.
Describe your main conclusion.
Crenolanib demonstrates significant anti-tumor activity in vitro in this genetically engineered mouse model of BSG.
Describe the importance of your findings and how they can be used by others.
The in vivo evaluation of Crenolanib with systemic and convection-enhanced delivery (CED) therapy in this model is currently ongoing.
This recapitulates the genetic alteration of 30-40% of DIPGs, which harbor amplification of PDGFR-a. Despite clinical trials using chemotherapy, novel targeted agents, and radiation, the natural history of this disease has not been significantly affected and 90% of children with DIPGs die within 2 years of diagnosis.
A first phase preclinical study was performed in a genetically engineered mouse model of Diffuse Intrinsic Pontine Glioma (DIPG). This model is driven by over-expression of PDGF-B ligand in nestin expressing cells in the brainstem of Ink4a-ARF deficient mice using the RCAS/tv-a gene transfer system.
BSG cells were harvested from the BSG model and treated in vitro. BrdU and MTT assays were completed to evaluate the anti-tumor activity of a small molecule inhibitor of PDGFR-a (Crenolanib) alone and in combination with rapamycin relative to vehicle-treated cells.
BrdU assays in vitro revealed the IC50 of Crenolanib to be 10nM in the PDGF-B-driven BSG tumor cells; the IC50 by MTT assays was 1.25µM. The IC50 of rapamycin by BrdU was 1 µM; when 10 nM Crenolanib and 1 µM rapamycin were combined and evaluated by BrdU assay, the inhibition of proliferation relative to vehicle-treated cells was greater than 90%.
This study used a specific model that may not translate to humans.
Crenolanib demonstrates significant anti-tumor activity in vitro in this genetically engineered mouse model of BSG.
The in vivo evaluation of Crenolanib with systemic and convection-enhanced delivery (CED) therapy in this model is currently ongoing.
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