Dissecting Molecular Mechanisms of Radioresistance Using in Vitro and in Vivo Brain Tumor Model Systems

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2012-07-16

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McEllin, Brian Matthew

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Abstract

Glioblastoma multiforme (GBM) are deadly brain tumors that are refractory to radiation and chemotherapy. Despite decades of work, little progress has been made in improving patient outcomes. Recent mapping of the GBM genome by the Cancer Genome Atlas Network revealed that these cancers commonly exhibit several signature mutations that promote gliomagenesis (e.g. EGFR amplification/activation, PTEN loss, p53 loss, Ink4a/Arf loss). How these genetic changes may modulate responses to radiation and chemotherapy is not well understood. To elucidate this relationship, genetically defined mouse models have been used for both in vitro and in vivo analysis. Work has uncovered novel links between oncogenic signaling and DNA repair pathways. First, activation of the Akt pathway by EGFRvIII, a constitutively active form of EGFR, promotes DNA double strand break repair by non-homologous end joining in astrocytes and glioma cell lines. This results in faster repair and increased radioresistance, both in vitro and in orthotopic GBM models. While activation of Akt by the loss of PTEN has similar results, data shows that PTEN loss reduces resistance to agents that induce replication-associated DSBs. This phenotype is due to reduced levels of homologous recombination, as astrocytes show increased radial chromosome aberrations and decreased sister chromatid exchanges after PTEN loss. These results have exciting implications, as it has identified two potential new therapeutic strategies for improving treatment in subsets of GBM patients. The cancer stem cell hypothesis postulates that cancers are organized similar to endogenous stem cell compartments, composed of a self-renewing cancer stem cell and other more “differentiated”, non-stem progeny. To determine how key GBM mutations affect the different cell types in GBM, I used the adult neural stem cell compartment as a reductionist model of a tumor. Surprisingly, data demonstrated that quiescent stem cells showed inherent resistance, even in a wild type mouse. In addition, stem cell-specific p53 loss increases radioresistance only in a subset of non-dividing progenitors, while proliferating progenitors remain sensitive to radiation. This model has offered novel insight into the effect of key pathways deregulated in GBM and how they impact different cell types.

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