TrkB inhibition by GNF-4256 slows growth and enhances chemotherapeutic efficacy in neuroblastoma xenografts

• Published in: Cancer chemotherapy and pharmacology Vol. 75; no. 1; pp. 131 - 141
• Main Authors: Croucher, Jamie L., Iyer, Radhika, Li, Nanxin, Molteni, Valentina, Loren, Jon, Gordon, W. Perry, Tuntland, Tove, Liu, Bo, Brodeur, Garrett M.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.01.2015; Springer Nature B.V
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Camptothecin - administration & dosage; Camptothecin - adverse effects; Camptothecin - analogs & derivatives; Camptothecin - pharmacology; Camptothecin - therapeutic use; Cancer Research; Cell Line, Tumor; Cell Survival - drug effects; Dacarbazine - administration & dosage; Dacarbazine - adverse effects; Dacarbazine - analogs & derivatives; Dacarbazine - pharmacology; Dacarbazine - therapeutic use; Dose-Response Relationship, Drug; Drugs, Investigational - administration & dosage; Drugs, Investigational - pharmacokinetics; Drugs, Investigational - pharmacology; Drugs, Investigational - therapeutic use; Half-Life; Humans; Medicine; Medicine & Public Health; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - metabolism; Mice, Nude; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - metabolism; Neuroblastoma - blood; Neuroblastoma - drug therapy; Neuroblastoma - metabolism; Neuroblastoma - pathology; Oncology; Original Article; Pharmacology/Toxicology; Phosphorylation - drug effects; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein Processing, Post-Translational - drug effects; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - metabolism; Receptor, trkB; Survival Analysis; Tumor Burden - drug effects; Xenograft Model Antitumor Assays; Signaling; TrkB; Neuroblastoma; Growth inhibition
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-014-2627-1

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 50 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.