The multikinase inhibitor EC‐70124 synergistically increased the antitumor activity of doxorubicin in sarcomas

Abstract

Cytotoxic drugs like doxorubicin remain as the most utilized agents in sarcoma treatment. However, advanced sarcomas are often resistant, thus stressing the need for new therapies aimed to overcome this resistance. Multikinase inhibitors provide an efficient way to target several pro‐tumorigenic pathways using a single agent and may constitute a valuable strategy in the treatment of sarcomas, which frequently show an aberrant activation of pro‐tumoral kinases. Therefore, we studied the antitumor activity of EC‐70124, an indolocarbazole analog that have demonstrated a robust ability to inhibit a wide range of pro‐survival kinases. Evaluation of the phospho‐kinase profile in cell‐of‐origin sarcoma models and/or sarcoma primary cell lines evidenced that PI3K/AKT/mTOR, JAK/STAT or SRC were among the most highly activated pathways. In striking contrast with the structurally related drug midostaurin, EC‐70124 efficiently prevented the phosphorylation of these targets and robustly inhibited proliferation through a mechanism associated to the induction of DNA damage, cell cycle arrest and apoptosis. In addition, EC‐70124 was able to partially reduce tumor growth in vivo. Importantly, this compound inhibited the expression and activity of ABC efflux pumps involved in drug resistance. In line with this ability, we found that the combined treatment of EC‐70124 with doxorubicin resulted in a synergistic cytotoxic effect in vitro and an increased antitumor activity of this cytotoxic drug in vivo. Altogether, these results uncover the capability of the novel multikinase inhibitor EC‐70124 to counteract drug resistance in sarcoma and highlight its therapeutic potential when combined with current treatments.

New Chondrosarcoma Cell Lines with Preserved Stem Cell Properties to Study the Genomic Drift During In Vitro/In Vivo Growth

“…For subcutaneous (s.c.) inoculations in the flanks of the mice, 5 × 10 5 cells mixed 1:1 with BD Matrigel Matrix High Concentration (Becton Dickinson-BD Biosciences, Erembodegem, Belgium) previously diluted 1:1 in culture medium were injected. Tumor volume was determined using a caliper as previously described [31]. One month after inoculation, mice were sacrificed by CO 2 asphyxiation and tumors were extracted and processed for histological analysis.…”

Mithramycin delivery systems to develop effective therapies in sarcomas

“…Once tumours reached approximately 100 mm 3 , the mice were randomly assigned (n = 5 per group) to receive the following intravenous treatments twice a week (6 doses): vehicle (PBS), 1 mg/Kg MTM, 2 mg/Kg MTM, 1 mg/kg MTM-LIP or 2 mg/Kg MTM-LIP. Mean tumour volume differences between groups were determined using a caliper as described [ 58 ]. Relative tumour volume (RTV) for every xenograft was calculated as follows: RTV = tumour volume at day of measurement (V t )−tumour volume at the beginning of the treatment (V o ).…”

Addressing Doxorubicin Resistance in Bone Sarcomas Using Novel Drug-Resistant Models

“…In addition, the efficacy of the treatment of osteosarcoma and chondrosarcoma with the multiple kinase inhibitor Lenvatinib, in combination with the anti-PD-1 antibody pembrolizumab, or ifosfamide/etoposide, is currently being evaluated (NCT04784247) [ 29 ]. Moreover, other drugs able to target several pro-tumoral pathways at once have demonstrated potent anti-tumor activities in sarcomas alone or in combination with current treatments [ 30 , 31 ]. Among them, G-C rich DNA-binding compounds, such as mithramycin (MTM) and its analog EC-8042, have demonstrated a potent anti-stemness activity in sarcomas [ 32 , 33 , 34 ].…”