AZ64 inhibits TrkB and enhances the efficacy of chemotherapy and local radiation in neuroblastoma xenografts

摘要: Neuroblastoma is a common pediatric tumor characterized by clinical heterogeneity. Because it derived from sympathetic neuroblasts, the NTRK family of neurotrophin receptors plays an integral role in neuroblastoma cell survival, growth, and differentiation. Indeed, high expression NTRK1 associated with favorable features outcome, whereas NTRK2 its ligand, brain-derived neurotrophic factor (BDNF), are unfavorable outcome. AZ64 (Astra Zeneca) potent selective inhibitor tyrosine kinases that blocks phosphorylation at nanomolar concentrations. To determine preclinical activity AZ64, we performed intervention trials xenograft model NTRK2-overexpressing neuroblastomas. alone significantly inhibited growth compared to vehicle-treated animals (p = 0.0006 for size). Furthermore, combination conventional chemotherapeutic agents, irinotecan temozolomide (irino–temo), showed enhanced anti-tumor efficacy irino–temo [(p < 0.0001 size, p 0.0005 event-free survival (EFS)]. We also assessed local radiation therapy (RT) on hindlimb model, RT was increased when were treated simultaneously EFS). conclude can inhibit NTRK-expressing neuroblastomas both vitro vivo. More importantly, enhance chemotherapy as well RT, presumably inhibition NTRK2/BDNF autocrine pathway.