PMID- 25394774 OWN - NLM STAT- MEDLINE DCOM- 20150303 LR - 20181202 IS - 1432-0843 (Electronic) IS - 0344-5704 (Print) IS - 0344-5704 (Linking) VI - 75 IP - 1 DP - 2015 Jan TI - TrkB inhibition by GNF-4256 slows growth and enhances chemotherapeutic efficacy in neuroblastoma xenografts. PG - 131-41 LID - 10.1007/s00280-014-2627-1 [doi] AB - PURPOSE: Neuroblastoma (NB) is one of the most common and deadly pediatric solid tumors. NB is characterized by clinical heterogeneity, from spontaneous regression to relentless progression despite intensive multimodality therapy. There is compelling evidence that members of the tropomyosin receptor kinase (Trk) family play important roles in these disparate clinical behaviors. Indeed, TrkB and its ligand, brain-derived neurotrophic factor (BDNF), are expressed in 50-60 % of high-risk NBs. The BDNF/TrkB autocrine pathway enhances survival, invasion, metastasis, angiogenesis and drug resistance. METHODS: We tested a novel pan-Trk inhibitor, GNF-4256 (Genomics Institute of the Novartis Research Foundation), in vitro and in vivo in a nu/nu athymic xenograft mouse model to determine its efficacy in inhibiting the growth of TrkB-expressing human NB cells (SY5Y-TrkB). Additionally, we assessed the ability of GNF-4256 to enhance NB cell growth inhibition in vitro and in vivo, when combined with conventional chemotherapeutic agents, irinotecan and temozolomide (Irino-TMZ). RESULTS: GNF-4256 inhibits TrkB phosphorylation and the in vitro growth of TrkB-expressing NBs in a dose-dependent manner, with an IC(5)(0) around 7 and 50 nM, respectively. Furthermore, GNF-4256 inhibits the growth of NB xenografts as a single agent (p < 0.0001 for mice treated at 40 or 100 mg/kg BID, compared to controls), and it significantly enhances the antitumor efficacy of irinotecan plus temozolomide (Irino-TMZ, p < 0.0071 compared to Irino-TMZ alone). CONCLUSIONS: Our data suggest that GNF-4256 is a potent and specific Trk inhibitor capable of significantly slowing SY5Y-TrkB growth, both in vitro and in vivo. More importantly, the addition of GNF-4256 significantly enhanced the antitumor efficacy of Irino-TMZ, as measured by in vitro and in vivo growth inhibition and increased event-free survival in a mouse xenograft model, without additional toxicity. These data strongly suggest that inhibition of TrkB with GNF-4256 can enhance the efficacy of current chemotherapeutic treatment for recurrent/refractory high-risk NBs with minimal or no additional toxicity. FAU - Croucher, Jamie L AU - Croucher JL AD - Oncology Research, The Children's Hospital of Philadelphia, CTRB Rm. 3018, 3501 Civic Center Blvd., Philadelphia, PA, 19104-4302, USA. FAU - Iyer, Radhika AU - Iyer R FAU - Li, Nanxin AU - Li N FAU - Molteni, Valentina AU - Molteni V FAU - Loren, Jon AU - Loren J FAU - Gordon, W Perry AU - Gordon WP FAU - Tuntland, Tove AU - Tuntland T FAU - Liu, Bo AU - Liu B FAU - Brodeur, Garrett M AU - Brodeur GM LA - eng GR - R01 CA094194/CA/NCI NIH HHS/United States GR - CA-094194/CA/NCI NIH HHS/United States PT - Comparative Study PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20141114 PL - Germany TA - Cancer Chemother Pharmacol JT - Cancer chemotherapy and pharmacology JID - 7806519 RN - 0 (Antineoplastic Agents) RN - 0 (Drugs, Investigational) RN - 0 (Membrane Glycoproteins) RN - 0 (Neoplasm Proteins) RN - 0 (Protein Kinase Inhibitors) RN - 7673326042 (Irinotecan) RN - 7GR28W0FJI (Dacarbazine) RN - EC 2.7.10.1 (Protein-Tyrosine Kinases) RN - EC 2.7.10.1 (Receptor, trkB) RN - EC 2.7.10.1 (tropomyosin-related kinase-B, human) RN - XT3Z54Z28A (Camptothecin) RN - YF1K15M17Y (Temozolomide) SB - IM MH - Animals MH - Antineoplastic Agents/administration & dosage/pharmacokinetics/pharmacology/*therapeutic use MH - Antineoplastic Combined Chemotherapy Protocols/administration & dosage/adverse effects/pharmacology/therapeutic use MH - Camptothecin/administration & dosage/adverse effects/analogs & derivatives/pharmacology/therapeutic use MH - Cell Line, Tumor MH - Cell Survival/drug effects MH - Dacarbazine/administration & dosage/adverse effects/analogs & derivatives/pharmacology/therapeutic use MH - Dose-Response Relationship, Drug MH - Drugs, Investigational/administration & dosage/pharmacokinetics/pharmacology/*therapeutic use MH - Half-Life MH - Humans MH - Irinotecan MH - Membrane Glycoproteins/*antagonists & inhibitors/metabolism MH - Mice, Nude MH - Neoplasm Proteins/*antagonists & inhibitors/metabolism MH - Neuroblastoma/blood/*drug therapy/metabolism/pathology MH - Phosphorylation/drug effects MH - Protein Kinase Inhibitors/administration & dosage/pharmacokinetics/pharmacology/*therapeutic use MH - Protein Processing, Post-Translational/drug effects MH - Protein-Tyrosine Kinases/*antagonists & inhibitors/metabolism MH - Receptor, trkB MH - Survival Analysis MH - Temozolomide MH - Tumor Burden/drug effects MH - Xenograft Model Antitumor Assays PMC - PMC4282593 MID - NIHMS642579 EDAT- 2014/11/15 06:00 MHDA- 2015/03/04 06:00 PMCR- 2016/01/01 CRDT- 2014/11/15 06:00 PHST- 2014/05/05 00:00 [received] PHST- 2014/11/06 00:00 [accepted] PHST- 2014/11/15 06:00 [entrez] PHST- 2014/11/15 06:00 [pubmed] PHST- 2015/03/04 06:00 [medline] PHST- 2016/01/01 00:00 [pmc-release] AID - 10.1007/s00280-014-2627-1 [doi] PST - ppublish SO - Cancer Chemother Pharmacol. 2015 Jan;75(1):131-41. doi: 10.1007/s00280-014-2627-1. Epub 2014 Nov 14.