Abstract
The purpose of the study was to evaluate the relationship between the levels of transcription factor, vascular endothelial growth factor (VEGF), serine/threonine-protein kinase (m-TOR), proteasome and calpain activities and the response to everolimus therapy in patients with disseminated renal cell carcinoma. Material and methods. The study included 18 patients with disseminated renal cell carcinoma. The expression of transcription and growth factors was studied using an immune enzymatic assay. Proteasome and calpain activities were evaluated using a fluorometric method. Results. Partial regression and stable disease were observed in 14 (78.8 %) of patients (tumor regression in 22.2 % of patients, stable disease in 56.6 % of patients). Disease progression occurred in 4 (22.2 %) of cases. The objective response to therapy with m-TOR inhibitor was observed in patients with high levels of NF-κB and HIF-1transcription factors, VEGF, VEGFR2 as well as with increased proteasome activity before treatment. Treatment response was also associated with low expression of phospho-m-TOR protein kinase. Conclusion. Additional predictive molecular markers of response to targeted therapy with evorolimus were revealed.
Highlights
The purpose of the study was to evaluate the relationship between the levels of transcription factor, vascular endothelial growth factor (VEGF), serine/threonine-protein kinase (m-TOR), proteasome and calpain activities and the response to everolimus therapy in patients with disseminated renal cell carcinoma
The objective response to therapy with m-TOR inhibitor was observed in patients with high levels of NF-κB and HIF-1transcription factors, VEGF, VEGFR2 as well as with increased proteasome activity before treatment
Treatment response was associated with low expression of phospho-m-TOR protein kinase
Summary
МОЛЕКУЛЯРНЫЕ ПОКАЗАТЕЛИ факторов, сосудистого эндотелиального фактора роста, его рецептора, серин/треониновой протеинкиназы m-TOR, активности протеасом и кальпаинов у больных с диссеминированным раком почки на фоне проведения таргетной терапии эверолимусом. Комбинированное лечение пациентов предполагало проведение предоперационной таргетной терапии эверолимусом в дозе 10 мг ежедневно в течение двух месяцев, с последующим выполнением паллиативной нефрэктомии. В опухолевом материале определяли активность протеасом и кальпаинов, а также количественное содержание VEGF, VEGFR2, HIF-1α, NF-κBp50 и NF-κBp65. Химотрипсинподобную активность протеасом определяли в гомогенатах опухолевых тканей по гидролизу флуорогенного олигопептида N-Succinyl-Leu-LeuVal-Tyr-7-Amido-4-Methylcoumarin, утилизирующегося химотрипсинподобными центрами протеасом [6], на флуориметре «Hitachi-850» (Япония) при длине волны возбуждения 380 нм и эмиссии 440 нм. Реакционная смесь для определения активности 20S протеасом содержала 20 мМ трис-HCl (pH=7,5), 1 мМ дитиотреитол, 30 мкМ N-Succinyl-Leu-LeuVal-Tyr-7-Amido-4-Methylcoumarin. Удельную активность протеасом выражали в единицах активности на 1 мг белка.
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