pd-0325901 and Brain-Neoplasms

Identifying cellular programs that drive cancers to be stem-like and treatment resistant is critical to improving outcomes in patients. Here, we demonstrate that constitutive extracellular signal-regulated kinase 1/2 (ERK1/2) activation sustains a stem-like state in glioblastoma (GBM), the most common primary malignant brain tumor. Pharmacological inhibition of ERK1/2 activation restores neurogenesis during murine astrocytoma formation, inducing neuronal differentiation in tumorspheres. Constitutive ERK1/2 activation globally regulates miRNA expression in murine and human GBMs, while neuronal differentiation of GBM tumorspheres following the inhibition of ERK1/2 activation requires the functional expression of miR-124 and the depletion of its target gene SOX9. Overexpression of miR124 depletes SOX9 in vivo and promotes a stem-like-to-neuronal transition, with reduced tumorigenicity and increased radiation sensitivity. Providing a rationale for reports demonstrating miR-124-induced abrogation of GBM aggressiveness, we conclude that reversal of an ERK1/2-miR-124-SOX9 axis induces a neuronal phenotype and that enforcing neuronal differentiation represents a therapeutic strategy to improve outcomes in GBM.

Topics: Animals; Astrocytoma; Benzamides; Brain Neoplasms; Cell Differentiation; Cell Line, Tumor; Cell Survival; Diphenylamine; Disease Progression; Female; Glioblastoma; Humans; Male; MAP Kinase Signaling System; Mice, Nude; MicroRNAs; Neoplasm Invasiveness; Neoplastic Stem Cells; Neurogenesis; Neurons; Phenotype; Protein Kinase Inhibitors; Radiation Tolerance; SOX9 Transcription Factor

The RAS/RAF mitogen-activated protein kinase pathway (MAPK) is highly active in many tumor types including the majority of high-grade gliomas and expression of activated RAS or RAF in neural progenitor cells combined with either AKT activation or Ink4a/Arf loss leads to the development of high-grade gliomas in vivo. This strongly suggests that this pathway is necessary for glioma formation and maintenance. To further define the role of this pathway in the development of high-grade gliomas, we used the established RCAS/TVA glioma mouse model to test the ability of activated MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK), a RAF effector, to induce tumors in vivo in the context of activated AKT or Ink4a/Arf loss. Although expression of activated MEK alone in neural progenitor cells is not sufficient for tumorigenesis, the combination of activated MEK and AKT or MEK with Ink4a/Arf loss is transforming. The data reveal that activation of the classical RAS/MAPK pathway, which is mediated through MEK, leads to the development of high-grade gliomas in vivo and suggest that MEK may be a relevant target for glioma therapy. To test this, we treated both mouse and human glioma cells with the MEK inhibitor PD0325901. Although this treatment induced apoptosis in a significant percentage of the cells, the effect was enhanced by combined treatment with the phosphatidylinositol 3-kinase (PI3K)/mTOR inhibitor NVP-BEZ235. Our results demonstrate that combined inhibition of MEK and PI3K/mTOR is a rational strategy for the treatment of high-grade gliomas and may be an effective adjuvant therapy for this disease.

Topics: Animals; Apoptosis; Benzamides; Brain Neoplasms; Cyclin-Dependent Kinase Inhibitor p16; Diphenylamine; Extracellular Signal-Regulated MAP Kinases; Genes, ras; Glioma; Humans; Imidazoles; MAP Kinase Signaling System; Mice; Mice, Transgenic; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Neoplasms; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Quinolines

Malignant astrocytic brain tumors are among the most lethal cancers. Quiescent and therapy-resistant neural stem cell (NSC)-like cells in astrocytomas are likely to contribute to poor outcome. Malignant oligodendroglial brain tumors, in contrast, are therapy sensitive. Using magnetic resonance imaging (MRI) and detailed developmental analyses, we demonstrated that murine oligodendroglioma cells show characteristics of oligodendrocyte progenitor cells (OPCs) and are therapy sensitive, and that OPC rather than NSC markers enriched for tumor formation. MRI of human oligodendroglioma also suggested a white matter (WM) origin, with markers for OPCs rather than NSCs similarly enriching for tumor formation. Our results suggest that oligodendroglioma cells show hallmarks of OPCs, and that a progenitor rather than a NSC origin underlies improved prognosis in patients with this tumor.

Topics: Animals; Antigens; Benzamides; Brain Neoplasms; Cell Differentiation; Cell Line, Tumor; Dacarbazine; Diphenylamine; Humans; Mice; Mitogen-Activated Protein Kinases; Neural Stem Cells; Oligodendroglia; Oligodendroglioma; Oncogene Proteins v-erbB; Proteoglycans; Temozolomide; Tumor Suppressor Protein p53