Abstract 5430: Frizzled-1 receptor, a potential therapeutic target for atypical teratoid rhabdoid tumor

Abstract

Abstract Atypical Teratoid Rhabdoid Tumors (ATRTs) are aggressive tumor types in the field of pediatric neuro-oncology that need new therapeutic strategies since they are associated with significantly worse overall prognosis than other pediatric tumors. A characteristic feature of ATRTs is usually an aberration of SMARCB1/INI1/hSNF5 gene. One of the important developmental pathways for cellular development is the Wnt pathway. Wnt proteins are a family of 19 secreted glycoproteins and act as ligands that bind transmembrane receptors such as the Frizzled receptors. There are 10 known Frizzled receptors, and the binding of a specific Wnt ligand to a specific Frizzled receptor plays a crucial role in the regulation of diverse cellular processes. Perturbation of the activities of Wnt ligands can result in defects in embryonic development and diseased states such as cancer. In our preliminary transcriptome analyses results, Wnt5b and Frizzled-1 receptor (Fz-1) were significantly upregulated in 20 ATRT samples and 3 ATRT cell lines. The binding of Wnt5b with Fz-1 was further confirmed by immunoprecipitation and Western blotting analyses. Treatment of ATRT cells with Fz-1 specific siRNA did not indicate a significant decrease in cell viability. Similarly treatment of ATRT cells with a Fz-1 specific monoclonal antibody (Fz-1Mab) also did not indicate significant decrease in cell viability. However, in this study treatment of cells with a combination of Fz-1 specific siRNA and Fz-1Mab indicated a significant decrease in cell viability. A dose response analysis was performed over time to test various doses of Fz-1Mab with constant Fz-1 siRNA concentrations; a cell titre glo assay was then performed to assess cell viability. The physiologically relevant Fz-1Mab dose was then used to assess the effects of using this combination treatment on Fz-1 and Wnt5b protein levels. A decrease in Fz-1 and Wnt5b protein levels when Fz-1 receptor is blocked by siRNA and Mab indicates that Wnt5b bound to Fz-1 receptor plays an important role in ATRT disease etiology and could be a therapeutic target. Citation Format: Madhavi Chakravadhanula, Victor Ozols, Chris Hampton, Ratan Bhardwaj. Frizzled-1 receptor, a potential therapeutic target for atypical teratoid rhabdoid tumor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5430. doi:10.1158/1538-7445.AM2014-5430