High-risk
neuroblastoma is a rapidly growing
tumor with a survival rate below 50%. A new treatment strategy is to administer chemotherapeutic drugs metronomically, i.e., at lower doses and frequent intervals. The aim of the study was to investigate the effects of
GMX1777, a chemotherapeutic
drug affecting cellular energy metabolism, in a mouse model for high-risk
neuroblastoma. Female SCID mice were injected s.c. with MYCN-amplified human
neuroblastoma cells and randomized to either treatment with
GMX1777 or vehicle. In some animals, treatment was discontinued allowing
tumor relapse. Treatment response was evaluated using the pediatric preclinical testing program (
PPTP). Immunohistochemistry and qRT-PCR was performed on
tumor cryosections to investigate the microscopic and molecular changes in
tumors in response to
GMX1777. Despite an increase in vessel density,
tumor regression and a high group response score according to
PPTP criteria was induced by
GMX1777 without inducing drug resistance. Treatment resulted in inhibition of
tumor cell proliferation, vessel maturation, reduced
hypoxia, increased infiltration of MHC class II negative macrophages and expansion of the nonvascular stromal compartment. Decreased stromal
VEGF-A and PDGF-B
mRNA in response to treatment together with the structural data suggest a "deactivation" or "silencing" of the
tumor stroma as a paracrine entity. In conclusion,
GMX1777 was highly efficient against high-risk
neuroblastoma xenografts through modulation of both the
tumor cell and stromal compartment.