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

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Abstract

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

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Acknowledgments

This work was supported in part by grants from the NIH (CA-094194, CA-097323; GMB), the Richard and Nancy Wolfson Young Investigator Fund (JEM), the St. Baldrick’s Foundation (CRV), and the Audrey E. Evans Endowed Chair in Molecular Oncology (GMB).

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Authors and Affiliations

  1. Division of Oncology, Children’s Hospital of Philadelphia, Colket Translational Research Building, Rm. 3018, 3501 Civic Center Blvd., Philadelphia, PA, 19104-4302, USA

    Radhika Iyer, Carly R. Varela, Jane E. Minturn, Ruth Ho, Anisha M. Simpson, Jennifer E. Light, Audrey E. Evans & Garrett M. Brodeur

  2. Biostatistics and Data Management Core, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Huaqing Zhao

  3. The Department of Pediatrics, The University of Pennsylvania, Philadelphia, PA, 19104, USA

    Carly R. Varela, Jane E. Minturn, Audrey E. Evans & Garrett M. Brodeur

  4. AstraZeneca, Pharmaceuticals, 35 Gatehouse Drive, Waltham, MA, 02451, USA

    Kenneth Thress & Jeffrey L. Brown

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  1. Radhika Iyer
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  2. Carly R. Varela
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  8. Huaqing Zhao
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  9. Kenneth Thress
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  11. Garrett M. Brodeur
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Correspondence to Garrett M. Brodeur.

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Radhika Iyer and Carly R. Varela contributed equally to this manuscript.

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Iyer, R., Varela, C.R., Minturn, J.E. et al. AZ64 inhibits TrkB and enhances the efficacy of chemotherapy and local radiation in neuroblastoma xenografts. Cancer Chemother Pharmacol 70, 477–486 (2012). https://doi.org/10.1007/s00280-012-1879-x

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