Human cancers do not behave as isolated collections of neoplastic cells but as a complex multicellular system, in which malignant cells establish bidirectional communication with neighbouring non-malignant cells. This interplay between tumour cells and tumour microenvironment influences tumour proliferation and metastasis. Furthermore, the microenvironment can also alter the response of tumours to diverse therapeutics. Therefore, targeting the tumour microenvironment has become an important approach in cancer drug discovery. Glioblastomas (GBM) are among the most lethal and least successfully treated brain tumours. Accumulating evidence suggests that inflammation in the GBM microenvironment strongly contributes to the fatality of this cancer. Brain tumours contain high levels of inflammatory cytokines, in particular interleukins (IL) IL-1β, IL-6 and IL-8, which play a prominent role in promoting GBM proliferation, migration and invasion.
p38 mitogen-activated protein kinase (MAPK) plays a critical role in the development and amplification of inflammation accompanying various CNS disorders. Using p38 MAPK inhibitors, we investigated whether p38 MAPK inhibition can reduce the formation of an inflammatory glioblastoma microenvironment and attenuate aggressive phenotype of GBM cells. We also tested p38 MAPK inhibitors in glioblastoma cells carrying epidermal growth factor receptor vIII mutation (EGFRvIII) as approximately 40-50% of glioblastomas are characterized by EGFR gene amplifications, with half of these co-expressing the constitutively activeEGFRvIII mutant; all of which are implicated in tumour growth, invasion and poor response to therapy. Results from our studies indicate that inflammatory microenvironment is a hallmark of GBMs, and that anti-inflammatory kinase inhibitors may alter GBM progression through modulation of cytokines levels in the microenvironment. The outcomes of these studies will be presented.