Abstract
Abstract Purpose: Neuroblastoma (NB) is one of the most common and deadly solid tumors of childhood. The Trk family of neurotrophin receptors plays an important role in clinical behavior of NBs. Overexpression of TrkB and its ligand, BDNF, is associated with poor prognosis. We wanted to determine if RXDX-101, an oral pan-TRK, ROS1 and ALK inhibitor, would be effective in our NB xenograft model, either alone or in combination with conventional chemotherapy. Experimental Design: We tested the in vitro effects of RXDX-101 as a single agent, or in combination with the chemotherapeutic agents irinotecan and temozolomide (Irino-TMZ), using a subclone of the SH-SY5Y NB cell line transfected with TrkB. We also examined in vivo growth inhibition of TrkB-expressing NB xenografts with RXDX-101 alone or in combination with Irino-TMZ. Results: RXDX-101 significantly inhibited growth of TrkB-expressing NB cells in vitro. Enhanced in vitro inhibition was observed when RXDX-101 was used in combination with Irino-TMZ. Single agent therapy with RXDX-101 resulted in significant tumor growth inhibition compared to control animals [p<0.0001 for event-free survival (EFS)]. The addition of RXDX-101 to Irino-TMZ also significantly improved the EFS of animals compared to vehicle or Irino-TMZ treated animals (p<0.0001 for combination vs. control, p = 0.0012 for combination vs. Irino-TMZ). Conclusions: We show that RXDX-101 inhibits growth of TrkB expressing NB cells in vitro and in vivo. Furthermore, RXDX-101 cotreatment enhanced the efficacy of conventional chemotherapy in our NB xenograft model. Our data suggest that RXDX-101 has potential for incorporation in clinical trials for NB and other Trk expressing tumors. Citation Format: Radhika Iyer, Rebecca L. Golden, Koumudi Naraparaju, Jamie L. Croucher, Peng Guan, Gang Li, Zachary Hornby, Garrett M. Brodeur. The TRK inhibitor RXDX-101 enhances the efficacy of temozolomide and irinotecan in a xenograft model of neuroblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5390. doi:10.1158/1538-7445.AM2015-5390
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