Targeting Sonic Hedgehog and atocyte Growth Factor Signaling in a Mouse Ther el of Medulloblastoma

ownload use of genetically engineered mice has provided insights into the molecular pathogenesis of the ric brain tumor medulloblastoma and revealed promising therapeutic targets. Ectopic expression of hedgehog (Shh) in cerebellar neural progenitor cells induces medulloblastomas in mice, and coexon of hepatocyte growth factor (HGF) enhances Shh-induced tumor formation. To determine whethh + HGF–driven medulloblastomas were responsive to Shh signaling blockade and whether ent response could be enhanced by combination therapy targeting both HGF and Shh signaling ays, we carried out a survival study in mice. We induced medulloblastomas by retrovirus-mediated sion of Shh and HGF, after which we treated the mice systemically with (a) HGF-neutralizing lonal antibody L2G7, (b) Shh signaling inhibitor cyclopamine, (c) Shh-neutralizing monoclonal an5E1, (d) L2G7 + cyclopamine, or (e) L2G7 + 5E1. We report that monotherapy targeting either HGF ing or Shh signaling prolonged survival and that anti-HGF therapy had a more durable response hh-targeted therapy. The effect of L2G7 + 5E1 combination therapy on cumulative survival was lent to that of L2G7 monotherapy and that of L2G7 + cyclopamine therapy was worse. The prinmechanism by which Shhand HGF-targeted therapies inhibited tumor growth was a potent apodeath response in tumor cells, supplemented by a weaker suppressive effect on proliferation. Our ation that combination therapy either failed to improve or even reduced survival in mice bearing HGF–induced medulloblastomas compared with monotherapy underscores the importance of preShh + clinical testing of molecular-targeted therapies in animal models of tumors in which the targeted pathways are known to be active. Mol Cancer Ther; 9(9); 2627–36. ©2010 AACR.