title: Control of proliferation in astrocytoma cells by the receptor tyrosine kinase/PI3K/AKT signaling axis and the use of PI-103 and TCN as potential anti-astrocytoma therapies.
abstract: A growing body of work suggests that astrocytomas and glioblastoma multiforme will require carefully tailored, molecularly targeted therapy for successful treatment. Recent efforts to comprehensively identify mutations and gene expression changes in glioblastoma have shown that mutation of NF1 is a common alteration in human glioblastoma. We have developed and characterized a panel of 14 tumor lines from grades II through IV astrocytomas developed from our Nf1-/+;Trp53-/+cis mouse model and have used this panel to characterize signal transduction pathways and inhibitors that are candidate therapeutic targets for astrocytoma and glioblastoma. We show that these tumors express platelet-derived growth factor receptor-α, epidermal growth factor receptor, and their respective ligands to varying degrees. We find that both the MEK and PI3K signaling pathways downstream of epidermal growth factor receptor and platelet-derived growth factor receptor-α are necessary for full proliferation of astrocytoma cells; however, inhibition of the PI3K pathway is more effective than inhibition of MEK at blocking cell growth. We have examined inhibitors of the PI3K/Akt/mTOR signaling pathway and find that PI-103 and TCN show particular promise for inhibiting growth in Nf1 and Trp53 mutant astrocytoma cells.
authors.affiliation: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD, USA
authors.forename: Demirkan B
authors.initials: DB
authors.lastname: Gürsel
authors.forename: Yvette S
authors.initials: YS
authors.lastname: Connell-Albert
authors.forename: Robert G
authors.initials: RG
authors.lastname: Tuskan
authors.forename: Theonie
authors.initials: T
authors.lastname: Anastassiadis
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Walrath
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Hawes
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Amlin-Van Schaick
authors.forename: Karlyne M
authors.initials: KM
authors.lastname: Reilly
mesh_terms: D000073:Acenaphthenes / Q000494:pharmacology*; D000818:Animals; D001254:Astrocytoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005663:Furans / Q000494:pharmacology*; D016514:Genes, Neurofibromatosis 1 / Q000502:physiology; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D058990:Molecular Targeted Therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D000073:Acenaphthenes; D066246:ErbB Receptors; D005663:Furans; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D011743:Pyrimidines; D020796:Receptor, Platelet-Derived Growth Factor alpha; D012265:Ribonucleotides; C522973:PI103; C014205:triciribine phosphate