Poster Presentation 25th Lorne Cancer Conference 2013

Evaluation of anti-inflammatory kinase inhibitors for glioblastoma therapy (#287)

Lenka Munoz 1 , Yiu T Yeung 2 , Melissa Tang 1 , Michael Buckland 3 , Ruiwen Heng 4 , Gilles Guillemin 4 5 , Thomas Grewal 2 , Hannu Haapasalo 6 , Joonas Haapasalo 6 , Herryawan Ryadi Eziwar Dyari 2 , Michael Murray 2
  1. School of Medical Sciences/Pharmacology, University of Sydney, Sydney, NSW, Australia
  2. Faculty of Pharmacy, University of Sydney, Sydney, NSW, Australia
  3. School of Medical Sciences/Pathology, University of Sydney, Sydney, NSW, Australia
  4. School of Medical Sciences/Pharmacology, University of New South Wales, Sydney, NSW, Australia
  5. Australian School of Advanced Medicine, Macquarie University, Sydney, NSW, Australia
  6. Department of Neuropathology, Tampere University Hospital, Tampere, Finland

Glioblastoma (GBM) is a fatal brain tumour and in terms of years of life lost, GBM tops the list, ahead of 17 other malignant cancers. An important factor that drives the invasion of transformed cells, including glioblastoma, is the development of an inflammatory microenvironment. Chronic inflammation in combination with infiltrated macrophages and oncogenic mutations contribute to up-regulate tumour-promoting cytokines which support migration, invasiveness and chemotherapy resistance [1].

p38 mitogen-activated protein kinase (MAPK) plays a critical role in the development and amplification of inflammation accompanying various CNS disorders. We investigated whether p38 MAPK inhibition can reduce the formation of an inflammatory glioblastoma microenvironment and attenuate aggressive phenotype of GBM cells [2]. We also tested p38 MAPK inhibitors in glioblastoma cells carrying epidermal growth factor receptor vIII mutation (EGFRvIII) as approximately 40% of glioblastomas are characterised by EGFR gene amplifications, with half of these co-expressing the constitutively active EGFRvIII mutant;all of which are implicated in tumour growth, invasion and poor response to therapy. Investigation of the molecular mechanism revealed that inhibition of the p38 MAPK downstream kinase MK2 and regulation of HuR nuclear-cytoplasm shuttling are responsible for the anti-inflammatory activity in cancer cells.

Pharmacological profiling of p38 MAPK and MK2 inhibitors in multiple in-vitro inflammation, migration, invasion and proliferation assays employing primary human microglia and GBM cells with varying EGFR profile will be presented. Tested anti-inflammatory kinase inhibitors improved chemosensitivity of GBM cells to temozolomide, the standard chemotherapeutic used in GBM therapy. Interestingly, MK2 inhibitors also showed potent anti-proliferative efficacy as single agents. Together, our data suggest that regulation of inflammatory GBM microenvironment with anti-inflammatory kinase inhibitors may represent a useful approach to improve the current management of this serious disease. Development of follow-up kinase inhibitors and investigation of MK2 in human GBM specimens will also be discussed. 

  1. Yeung YT et al (2012), Br J Pharmacol doi:10.1111/bph.12008
  2. Yeung et al (2012) J Neurooncol 109:35 - 44