title: A preclinical orthotopic model for glioblastoma recapitulates key features of human tumors and demonstrates sensitivity to a combination of MEK and PI3K pathway inhibitors.
abstract: Current therapies for glioblastoma multiforme (GBM), the highest grade malignant brain tumor, are mostly ineffective, and better preclinical model systems are needed to increase the successful translation of drug discovery efforts into the clinic. Previous work describes a genetically engineered mouse (GEM) model that contains perturbations in the most frequently dysregulated networks in GBM (driven by RB, KRAS and/or PI3K signaling and PTEN) that induce development of Grade IV astrocytoma with properties of the human disease. Here, we developed and characterized an orthotopic mouse model derived from the GEM that retains the features of the GEM model in an immunocompetent background; however, this model is also tractable and efficient for preclinical evaluation of candidate therapeutic regimens. Orthotopic brain tumors are highly proliferative, invasive and vascular, and express histology markers characteristic of human GBM. Primary tumor cells were examined for sensitivity to chemotherapeutics and targeted drugs. PI3K and MAPK pathway inhibitors, when used as single agents, inhibited cell proliferation but did not result in significant apoptosis. However, in combination, these inhibitors resulted in a substantial increase in cell death. Moreover, these findings translated into the in vivo orthotopic model: PI3K or MAPK inhibitor treatment regimens resulted in incomplete pathway suppression and feedback loops, whereas dual treatment delayed tumor growth through increased apoptosis and decreased tumor cell proliferation. Analysis of downstream pathway components revealed a cooperative effect on target downregulation. These concordant results, together with the morphologic similarities to the human GBM disease characteristics of the model, validate it as a new platform for the evaluation of GBM treatment.
authors.affiliation: Center for Advanced Preclinical Research, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors.forename: Rajaa
authors.initials: R
authors.lastname: El Meskini
authors.affiliation: Center for Advanced Preclinical Research, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Iacovelli
authors.affiliation: Center for Advanced Preclinical Research, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Kulaga
authors.affiliation: Center for Advanced Preclinical Research, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Gumprecht
authors.affiliation: Center for Advanced Preclinical Research, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors.forename: Philip L
authors.initials: PL
authors.lastname: Martin
authors.affiliation: Center for Advanced Preclinical Research, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors.forename: Maureen
authors.initials: M
authors.lastname: Baran
authors.affiliation: Center for Advanced Preclinical Research, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors.forename: Deborah B
authors.initials: DB
authors.lastname: Householder
authors.affiliation: Center for Advanced Preclinical Research, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA. Mouse Cancer Genetics Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors.forename: Terry
authors.initials: T
authors.lastname: Van Dyke
authors.affiliation: Center for Advanced Preclinical Research, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA. zweaverohler@mail.nih.gov.
authors.forename: Zoë
authors.initials: Z
authors.lastname: Weaver Ohler
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D005904:Glial Fibrillary Acidic Protein; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D005904:Glial Fibrillary Acidic Protein; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors
keywords: Apoptosis; Glioblastoma; Mouse model; PI3K and MEK inhibition