Beschreibung:
<jats:title>Abstract</jats:title>
<jats:p>Background: The non-canonical Wnt/planar cell polarity (PCP) pathway regulates cytoskeletal organization, migration and neuritogenesis. Signaling is characterized by activation of the GTPases Rho and Rac, and the downstream Rho-associated protein kinases (ROCKs). Neuroblastoma is a malignant embryonal tumor of the sympathetic nervous systems, often with poor prognosis. The need for novel therapeutic approaches is great. Genetic analyses have revealed mutations and aberrations in the regulators Rho/Rac in neuroblastoma. The aim of this study was to characterize the Wnt/PCP signaling and the effects of ROCK inhibition in neuroblastoma.</jats:p>
<jats:p>Methods: Cytotoxic activity of ROCK inhibitors was studied in cell viability assays. Morphology and invasion were studied with microscopy. The molecular mechanisms were characterized using cell- and molecular biology techniques. In vivo studies in mice were carried out to validate the therapeutic effects and toxicity.</jats:p>
<jats:p>Results: Several mediators in the pathway were differentially expressed in cell lines and patient samples. Using compounds blocking ROCK1 and ROCK2 activity revealed that the ROCK2 inhibitor HA-1077 effectively repressed proliferation and reduced cell viability in neuroblastoma. Additionally, HA-1077 inhibited migration and induced differentiation through initiating neural outgrowth. Furthermore, HA-1077 reduced the growth of established neuroblastoma xenografts in nude mice.</jats:p>
<jats:p>Conclusions: These results suggest that non-canonical Wnt signaling in general and ROCK in particular is a promising new therapeutic target for high-risk neuroblastoma.</jats:p>
<jats:p>Citation Format: Cecilia Dyberg, David Forsberg, Panos Papachristou, Jessika Lannerholm-Palm, Bjorn Helge Haug, Baldur Sveinbjörnsson, Hugo Lagercrantz, Per Kogner, John inge Johnsen, Malin Wickstrom. Targeting the Wnt/PCP signaling through ROCK: A new neuroblastoma drug target. [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 3110. doi:10.1158/1538-7445.AM2014-3110</jats:p>