942. Adenoviral Mediated Re-Expression of Wnt Antagonist Dkk-1 Induces Apoptosis and Suppresses Tumor Growth in Medulloblastoma

Abstract

Medulloblastoma comprises approximately 20% of all primary pediatric brain tumors. Advances in treatment with surgery, radiation and chemotherapy have resulted in a five-year survival rate of approximately 70% over the last 20 years. Unfortunately children less than 3 years of age continue to have significantly worse outcomes. Most importantly, the morbidity associated with these treatments can be devastating given their lack of specificity. To elucidate signaling pathways for potential directed therapy we sought to identify putative tumor suppressor genes down regulated by epigenetic mechanisms. Inappropriate epigenetic gene silencing results in the loss of critical regulators of proliferation and apoptotic pathways. We hypothesized that viral mediated re-expression of such epigenetically silenced tumor suppressor genes would result in suppression of tumor growth. A survey of epigenetically silenced genes identified the antagonist Dickkopf 1(Dkk1) as down-regulated medulloblastoma cell lines and in medulloblastoma patient samples; Dkk1 expression could be re-induced by histone de-acetylaseh inhibition. Importantly, re-expression of Dkk1via vector-mediated gene transfer caused medulloblastoma cell apoptosis and inhibited tumor formation in vitro as measured by colony formation on soft agar. Taken together our data implicate Wnt signaling as an important regulator of medulloblastoma pathogenesis, and suggest that re- introduction of Dkk1 may provide for therapeutic benefit in medulloblastoma patients.