Abstract 2095: Toxicity of selective allosteric FGFR2 inhibition in preclinical studies
| Autor: | Vadim A. Kashuro, Nataliya V. Lapina, Marina V. Melikhova, Olga A. Vakunenkova |
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| Rok vydání: | 2016 |
| Předmět: | |
| Zdroj: | Cancer Research. 76:2095-2095 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am2016-2095 |
| Popis: | Alofanib (RPT835, Ruspharmtech LLC) is a novel selective allosteric inhibitor binding to the extracellular domain of FGFR2. Alofanib had no direct effect on activation of FGFR1 and FGFR3 in vitro. Selective effect of the compound may reduce toxicity compared to multi-targeted VEGFR/FGFR or pan-FGFR inhibitors. This study characterizes the organ toxicity of alofanib in Sprague-Dawley rats and Chinchilla rabbits, and the reversibility of any treatment-induced effects. 240 rats and 30 rabbits received alofanib (0-40.5 and 0-21.6 mg/kg/day, respectively) intravenously on a consecutive daily dosing schedule for thirteen weeks. Clinical observations and laboratory parameters were recorded. Necropsy was conducted following treatment/recovery periods, and histologic examinations were performed. There was no treatment-related mortality, severe toxicity and significant changes in organs in the thirteen-week study. Alofanib was well-tolerated in vivo. Clinical signs of first injection (8.1 mg/kg) included moderate local irritative reaction and decreased activity during hour in rats. Clinical symptoms of toxicity were not observed over study. Animals were active. Body weight remained stable and it was comparable to vehicle groups. Abnormal electrocardiogram findings and blood pressure changes were not detected. It was notable that in the study, none of the hematologic changes was present at the end of the recovery period. Minimal significant decrease in ALT/AST, slight increase in alkaline phosphatase in male rats and mild increase in urea, decrease in chlorine in female rats were found throughout treatment period. Minimal significant decrease in albumin and chlorine was identified in rabbits. Rate of hyperphosphatemia, an on-target side-effect of pan-FGFR inhibitors, will be presented at the AACR Meeting. We conclude that toxicity of alofanib was mild in the thirteen-week study. Slight decrease of chlorine in blood was most common side effect. The final conclusion will be made after six-month study. This study was supported by a grant from the Skolkovo Foundation. Citation Format: Nataliya V. Lapina, Marina V. Melikhova, Olga A. Vakunenkova, Vadim A. Kashuro. Toxicity of selective allosteric FGFR2 inhibition in preclinical studies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2095. |
| Databáze: | OpenAIRE |
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