Sequential courses of anticancer target therapy lead to selection of drug-resistant cells, which results in continuous decrease of clinical response. Here we present a new approach for predicting effective combinations of target drugs, which act in a synergistic manner. Synergistic combinations of drugs may prevent or postpone acquired resistance, thus increasing treatment efficiency. We cultured human ovarian carcinoma SKOV-3 and neuroblastoma NGP-127 cancer cell lines in the presence of Tyrosine Kinase Inhibitors (Pazopanib, Sorafenib, and Sunitinib) and Rapalogues (Temsirolimus and Everolimus) for four months and obtained cell lines demonstrating increased drug resistance. We investigated gene expression profiles of intact and resistant cells by microarrays and analyzed alterations in 378 cancer-related signaling pathways using the bioinformatical platform Oncobox. This revealed numerous pathways linked with development of drug resistant phenotypes. Our approach is based on targeting proteins involved in as many as possible signaling pathways upregulated in resistant cells. We tested 13 combinations of drugs and/or selective inhibitors predicted by Oncobox and 10 random combinations. Synergy scores for Oncobox predictions were significantly higher than for randomly selected drug combinations. Thus, the proposed approach significantly outperforms random selection of drugs and can be adopted to enhance discovery of new synergistic combinations of anticancer target drugs.

49 Background: Gastrointestinal stromal tumours (GISTs) contain oncogenic KIT or PDGFRA tyrosine kinase (TK) mutations leading to disturbance of downstream signaling pathways that contribute to GIST pathogenesis. Additional genetic aberrations were found in GISTs, demonstrating the involvement of other genes important in tumor progression. The aim of the study was to evaluate the prognostic relevance of different TK mutations in GISTs and to analyze the additional genetic aberrations in GISTs according to mutational status. Methods: 180 GIST patients were examined for KIT (9, 11, 13, 17 exons) and PDGFRA mutations (12, 14, 18 exons) by direct sequencing of DNA obtained from microdissected tumor sections. Tumor tissue DNA from 44 GISTs patients was screened for loss of heterozygosity (LOH) at 11 microsatellite loci on 1p, 9p, 14q, 15q and 22q arms. Results: KIT and PDGFRA mutations were identified in 76.1% and 10% of GISTs, respectively. 13.9% GISTs had no mutations (wild type). Most of KIT mutations were located in exon 11 (65%) and exon 9 (9.4%). Prognostic significance of TK mutations was evaluated. There was a trend of better survival for patients with PDGFRA mutation then with KIT mutation or wild type GISTs. The higher overall survival prior to target therapy was shown for patients with duplication or point mutation in KIT exon 11 in comparison to exon 11 deletion. Analysis of LOH revealed allelic deletions in 85% of GISTs, more frequently at 14q arm. There was a different LOH pattern in subgroups of GISTs. GISTs with PDGFRA mutation and with KIT exon 11 point mutation had LOH at 14q, while GISTs with KIT exon 11 deletions revealed high LOH frequency also on 22q, 15q and 1p arms. LOH in wild type GISTs occurred on all chromosomes with low frequency. LOH on 9p was found exclusively in metastatic and recurrent GISTs. Specific gene loci of frequent LOH were identified on 9p, 15q and 22q that may be contributed to GIST progression. Conclusions: Specific mutations are associated with GISTs prognosis. Tumors with point mutations and duplications in KIT exon 11 are associated with a better survival then GISTs with other KIT mutations. Specific pattern of allelic deletions was identified in subgroups of GISTs according to type of mutation and tumor progression. No significant financial relationships to disclose.

No abstract

No abstract

Гастропанкреатодуоденальная резекция (ГПДР)-стандартный объем хирургического вмешательства при опухолевом поражении двенадцатиперстной кишки. Послеоперационные осложнения после ГПДР развиваются у 30-70% больных. По данным литературы, при неэпителиальных опухолях (за исключением лимфом) оправданы экономные операции. Обя зательными требованиями к хирургическому вмешательству являются отрицательные края резекции и сохранение целост ности капсулы опухоли. Цель исследования-оценка переносимости, безопасности и функциональности дистальной резекции двенадцатиперст ной кишки, методика которой разработана в НМИЦ онкологии им. Н.Н. Блохина. Материал и методы. В НМИЦ онкологии им. Н.Н. Блохина с 2006 по 2018 г. выполнено 10 дистальных резекций двенадца типерстной кишки по поводу ее опухолевого поражения, в том числе по поводу первичной опухоли у 8 больных, по поводу вторичной опухолевой инвазии извне у 2. В раннем послеоперационном периоде осложнения I-II степени (по классификации Clavien-Dindo) развились у 4 (40%) больных. Хирургическое осложнение II степени отмечено у 1 (10%) больного в виде панкреатического свища, который закрылся на фоне консервативного лечения. Несостоятельности культи двенадцатиперстной кишки и дуоденоеюноана стомоза, нарушения билиодинамики и/или стеноза анастомоза с замедлением эвакуации из желудка, а также летальных исходов во всех случаях не наблюдалось. Выводы. Дистальная резекция двенадцатиперстной кишки ассоциируется с низкой послеоперационной морбидностью, хорошей функциональностью и качеством жизни больных и является методом выбора у больных неэпителиальными и нейроэндокринными опухолями, а также при вторичной опухолевой инвазии двенадцатиперстной кишки извне. Ключевые слова: дистальная дуоденальная резекция, панкреатодуоденэктомия, нейроэндокринные опухоли.