Abstract 5038: Probing network fragilities in neuroblastoma by synergistic drug combinations.

Abstract

Abstract Neuroblastoma is the most common tumor in infants younger than 1 year of age and one of the most common solid tumors in childhood. The disease is highly variable: while spontaneous tumor regression occurs more often than in any other cancer type, patients with more severe variant face therapy-resistant recurrence. Therefore we have set out to develop new therapeutic approaches to the disease with a particular focus on aggressive subtypes. Using a high-throughput systems level approach we have identified a novel synergistic combination of approved drugs and compounds in clinical trials. Our initial screen assessed the potency of a panel of clinically applicable drugs by proliferation assays versus a defined panel of isogenic cell lines that are representative of the different neuroblastoma variants. We identified potential drugs combinations by three-dimensional dose response matrices and adopted Bliss values as a quantitative measure of the synergy. The striking synergy was observed in SH-SY5Y cell line using combinations of EGFR/HER2 inhibitors with the apoptosis inducing agents. We were able to validate the observation using colony formation assay. In contrast to single drug treatment, the combination completely abolished the clonogenic growth of neuroblastoma cells, showing the most tangible evidence of the synergy. In order to evaluate our results in more aggressive disease subtypes, we tested our combination in SH-SY5Y cell line with transiently overexpressed N-Myc and in N-Myc-amplified IMR5-75 cell line. Notably, even in this setting we could recapitulate our findings, suggesting that this combination of drugs is highly potent in the chemo-resistant tumor subtypes as well. The same effect was observed when we transiently overexpressed TrkA in SH-SY5Y, mimicking yet another neuroblastoma variant. Pursuing the exact mechanism of the synergy, we have tested the combination in breast cancer cells. To our surprise, the synergistic effect was still present in HER2 negative cell line, but completely absent in the HER2 positive one. We also exchanged the dual EGFR/HER2 inhibitor drug with more potent EGFR inhibitors to conclude that a combination seems to be specific to a particular set of compounds and not necessarily to their main target spectra. Our synergistic combination is highly potent in a large number of neuroblastoma conditions. Strong synergistic effect can be reached at doses much lower than required for the single drug treatment. Animal models that we are currently testing will enable quick translation of our data in clinics. Citation Format: Branka Radic, Uwe Rix, Stefan Kubicek, Giulio Superti-Furga. Probing network fragilities in neuroblastoma by synergistic drug combinations. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5038. doi:10.1158/1538-7445.AM2013-5038