Neuroblastoma is the most common and deadly solid tumor in children, but this tumor also has a very high propensity to undergo spontaneous differentiation or regression. Evidence suggests that the Trk family of neurotrophin receptors play a critical role in tumor behavior. Neuroblastomas expressing TrkA are biologically favorable and prone to spontaneous differentiation or regression. In contrast, Neuroblastomas expressing TrkB usually have MYCN amplification and are among the most aggressive and deadly tumors known. These tumors also express the TrkB ligand, resulting in an autocrine survival pathway. Unlike the TrkA-expressing tumors, exposure to ligand promotes survival under adverse conditions, but does not cause differentiation. We are exploring the biological basis for the very different behavior of neuroblastomas expressing these highly homologous neurotrophin receptors. We will also determine the consequences of blocking TrkA versus TrkB expressing tumors with the novel, Trk-targeted tyrosine kinase inhibitor CEP-2563.
Our specific aims are:
Specific Aim 1. Determine the differences in receptor structure, signaling and gene induction that distinguish the biological effects of TrkA versus TrkB expression in human neuroblastoma cells. Hypothesis: A fundamental difference in receptor structure, leading to differences in signaling. Immediate-early gene induction, and/or interactions with P75 explain the difference in biological behavior of TrkA- and TrkB expressing neuroblastomas.
Specific Aim 2. Analyze the consequences of TrkA or TrkB inhibition on neuroblastoma behavior and tumorigenicity. Hypothesis: Inhibition of TrkA will induce apoptosis, and inhibition of TrkB will decrease angiogenesis, tumorigenicity and resistance to chemotherapy. The successful completion of these studies should explain why the biological consequences of expressing TrkA versus TrkB are so different, and what portion of the receptor is responsible for this difference. We will also determine the efficacy of the novel tyrosine kinase inhibitor CEP-2563 in treating TrkA and TrkB expressing tumors. Given the increasing evidence for a role of Trk receptors in a variety of pediatric and adult tumors, these data would argue strongly for the utility of Trk receptor inhibition in therapy, alone or in combination.
| Brodeur, Garrett M (2018) Spontaneous regression of neuroblastoma. Cell Tissue Res 372:277-286 |
| Iyer, Radhika; Wehrmann, Lea; Golden, Rebecca L et al. (2016) Entrectinib is a potent inhibitor of Trk-driven neuroblastomas in a xenograft mouse model. Cancer Lett 372:179-86 |
| Ratner, Nancy; Brodeur, Garrett M; Dale, Russell C et al. (2016) The ""neuro"" of neuroblastoma: Neuroblastoma as a neurodevelopmental disorder. Ann Neurol 80:13-23 |
| Alferiev, Ivan S; Iyer, Radhika; Croucher, Jamie L et al. (2015) Nanoparticle-mediated delivery of a rapidly activatable prodrug of SN-38 for neuroblastoma therapy. Biomaterials 51:22-9 |
| Croucher, Jamie L; Iyer, Radhika; Li, Nanxin et al. (2015) TrkB inhibition by GNF-4256 slows growth and enhances chemotherapeutic efficacy in neuroblastoma xenografts. Cancer Chemother Pharmacol 75:131-41 |
| Iyer, Radhika; Croucher, Jamie L; Chorny, Michael et al. (2015) Nanoparticle delivery of an SN38 conjugate is more effective than irinotecan in a mouse model of neuroblastoma. Cancer Lett 360:205-12 |
| Brodeur, Garrett M; Bagatell, Rochelle (2014) Mechanisms of neuroblastoma regression. Nat Rev Clin Oncol 11:704-13 |
| Brodeur, Garrett M; Iyer, Radhika; Croucher, Jamie L et al. (2014) Therapeutic targets for neuroblastomas. Expert Opin Ther Targets 18:277-92 |
| Werner, Petra; Paluru, Prasuna; Simpson, Anisha M et al. (2014) Mutations in NTRK3 suggest a novel signaling pathway in human congenital heart disease. Hum Mutat 35:1459-68 |
| Redden, Robert A; Iyer, Radhika; Brodeur, Garrett M et al. (2014) Rotary bioreactor culture can discern specific behavior phenotypes in Trk-null and Trk-expressing neuroblastoma cell lines. In Vitro Cell Dev Biol Anim 50:188-93 |
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