New potential targets in medulloblastoma therapy : Studies on cellular mechanisms and mediators

Sammanfattning: Medulloblastoma is an embryonal tumour that mainly affects children. It is the most common malignant brain tumour in children and accounts for 15% of all childhood brain tumours. It most often presents in the cerebellum and is considered to be a disorder of normal development. Despite intensive multimodal therapy, survival in high-risk patients is still poor, and long-time survivors suffer from detrimental side effects. To improve outcome, new treatments based on a better understanding of medulloblastoma biology are needed. Prostaglandin E2 (PGE2) is a proinflammatory eicosanoid that is linked to cancer progression and development. It is formed from arachidonic acid through enzymatic conversion catalyzed by cyclooxygenases (COX-1/2). PGE2 promotes tumour growth by activating signalling pathways that control cell proliferation, invasion, apoptosis, angiogenesis and immunosuppression. We found that COX-2/PGE2 signalling is activated in medulloblastoma, and that PGE2 has an important role in medulloblastoma growth. Celecoxib, a selective COX-2 inhibitor, demonstrated promising effects against medulloblastoma tumour growth both alone and when combined with cytostatic drugs. Celecoxib potentiated the effect of the DNA alkylator temozolomide by downregulating MGMT expression and by inhibiting proliferation of CD15/CD133 positive medulloblastoma cells. Canonical Wnt signalling pathway and phosphoinositide-3-kinase (PI3K)/Akt pathway are crucial for normal cerebellar development. In medulloblastoma, activation of Wnt/beta-catenin and PI3K/Akt signalling are commonly observed. Our results show that PI3K/Akt-Wnt/beta-catenin cross-talk is important for medulloblastoma tumourigenesis. We demonstrated that OSU03012, a small molecule inhibitor of the PI3K/Akt signalling protein phosphoinositide-dependent protein kinase-1, suppresses medulloblastoma growth both in vitro and in vivo by interfering with GSK-3beta inactivation and beta-catenin activity. Furthermore, OSU03012 induced synergistic cytotoxicity when combined with chemotherapeutic drugs and augmented the antitumour effect of the mammalian target of rapamycin inhibitor CCI-779 in vivo. Human cytomegalovirus (HCMV) is an oncomodulatory virus that has recently been detected in tumours of different origin. We found a high prevalence of HCMV in medulloblastoma primary tumours and cell lines and showed that infection with HCMV upregulates production of PGE2 in medulloblastoma. Treatment with the antiviral drugs ganciclovir/valganciclovir or celecoxib inhibited medulloblastoma tumour growth both in vitro and in vivo, and the combined therapy demonstrated augmented effects. Based on our observations we suggest that HCMV may, indirectly through the activation of COX-2, be an etiological factor in medulloblastoma development. In summary, this thesis has identified PGE2/COX-2, the PI3K/Akt-Wnt/beta-catenin cross-talk and HCMV as novel targets in medulloblastoma. Compounds that inhibit these targets demonstrate promising effects in experimental models of medulloblastomas, supporting the rationale for clinical testing as novel adjuvant therapy for children with medulloblastoma.