The use of genetically engineered mice has provided insights into the molecular pathogenesis of the pediatric
brain tumor medulloblastoma and revealed promising therapeutic targets. Ectopic expression of Sonic hedgehog (Shh) in cerebellar neural progenitor cells induces
medulloblastomas in mice, and coexpression of
hepatocyte growth factor (HGF) enhances Shh-induced
tumor formation. To determine whether Shh + HGF-driven
medulloblastomas were responsive to Shh signaling blockade and whether treatment response could be enhanced by combination
therapy targeting both HGF and Shh signaling pathways, we carried out a survival study in mice. We induced
medulloblastomas by retrovirus-mediated expression of Shh and HGF, after which we treated the mice systemically with (a) HGF-neutralizing
monoclonal antibody L2G7, (b) Shh signaling inhibitor
cyclopamine, (c) Shh-neutralizing
monoclonal antibody 5E1, (d) L2G7 +
cyclopamine, or (e) L2G7 + 5E1. We report that monotherapy targeting either HGF signaling or Shh signaling prolonged survival and that anti-HGF
therapy had a more durable response than Shh-targeted
therapy. The effect of L2G7 + 5E1 combination
therapy on cumulative survival was equivalent to that of L2G7 monotherapy and that of L2G7 +
cyclopamine therapy was worse. The principal mechanism by which Shh- and HGF-targeted
therapies inhibited
tumor growth was a potent apoptotic death response in
tumor cells, supplemented by a weaker suppressive effect on proliferation. Our observation that combination
therapy either failed to improve or even reduced survival in mice bearing Shh + HGF-induced
medulloblastomas compared with monotherapy underscores the importance of preclinical testing of
molecular-targeted therapies in animal models of
tumors in which the targeted pathways are known to be active.