Strategies to increase effectiveness of growth factor receptors-targeted therapy in glioblastoma

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Oncology-Pathology

Sammanfattning: Gliomas are the most common glial neoplasms, accounting for nearly 70% of all primary brain tumours. The progression of low-grade gliomas into more aggressive tumours is supported by the abnormal function of several proto-oncogenes, including growth factor receptor tyrosine kinases (GFR-TKs). In paper I, we showed that the pharmacologic inhibition (using small molecule inhibitors) of IGF-1R, PDGFR and their intracellular signalling via PI3-K and ERK1/2 kinases had only modest or not antitumour activity in five glioblastoma cell lines (MO59J, MO59K, 8, 18 and 38). The ability of the ionizing radiation to improve the effect of the molecular targeted therapy was also investigated. Interaction between small inhibitors and ionizing radiation was mostly additive or subadditive, synergistic interaction was found in few analysed combinations. One explanation may be the interaction of the IGF-1R with PDGFR in maintenance the intracellular signalling activated. Therefore, a therapeutic strategy of co-targeting both IGF-1R and PDGFR has been taken into account. In two glioblastoma cell lines (18 and 38), we found that dual targeting of IGF-1R and PDGFR increased cell death in comparison to the inhibition of either receptor alone. In addition, co-inhibition of IGF-1R and PDGFR increased radiosensitivity in 18 cells but failed to intensify the effect of radiation in 38 cells. In glioblastoma cells, radiation induced cell death has been connected to the activation of c-Jun-NH2-terminal kinase-1 (JNK1). We found that JNK1 was weakly expressed in 38 cells while it had an elevated expression in 18 cells. Exposure to ionizing radiation induced JNK1 activation in 18 cells only, suggesting that in this cell line radiation-activated JNK1 may provide an anti-proliferative signalling parallel to receptors co-targeting. To test this hypothesis, glioblastoma cells were treated with dominant negative JNK1 (dnJNK1) and the response to radiation was assayed in the presence or absence of receptors co-inhibition. Indeed, dnJNK1 protected 18 cells against ×-radiation induced cell death. The dnJNK1 treatment did not influence radiation response of the 38 cell line, which expressed low levels of JNK1 (paper II). In conclusion, the combination of different targeted agents, or targeted agents and radiotherapy, seems to be a better treatment option than single agent therapy, with respect to the evident molecular heterogeneity of brain tumours. Nevertheless, a detail molecular understanding of the molecular pathogenesis of malignant gliomas is necessary to design an effective therapy against this stage of the disease.

  HÄR KAN DU HÄMTA AVHANDLINGEN I FULLTEXT. (följ länken till nästa sida)