Tyrosine kinase inhibitors (TKIs) are frequently used in combined therapy to enhance treatment efficacy and overcome drug resistance. The present study analyzed the effects of three inhibitors, sunitinib, gefitinib, and lapatinib, combined with iron-chelating agents, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) or di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC). Simultaneous administration of the drugs consistently resulted in synergistic and/or additive activities against the cell lines derived from the most frequent types of pediatric solid tumors. The results of a detailed analysis of cell signaling in the neuroblastoma cell lines revealed that TKIs inhibited the phosphorylation of the corresponding receptor tyrosine kinases, and thiosemicarbazones downregulated the expression of epidermal growth factor receptor, platelet-derived growth factor receptor, and insulin-like growth factor-1 receptor, leading to a strong induction of apoptosis. Marked upregulation of the metastasis suppressor N-myc downstream regulated gene-1 (NDRG1), which is known to be activated and upregulated by thiosemicarbazones in adult cancers, was also detected in thiosemicarbazone-treated neuroblastoma cells. Importantly, these effects were more pronounced in the cells treated with drug combinations, especially with the combinations of lapatinib with thiosemicarbazones. Therefore, these results provide a rationale for novel strategies combining iron-chelating agents with TKIs in therapy of pediatric solid tumors.
- Klíčová slova
- NDRG1, neuroblastoma, pediatric solid tumors, receptor tyrosine kinases, thiosemicarbazones, tyrosine kinase inhibitors,
- Publikační typ
- časopisecké články MeSH
The specific targeting of signal transduction by low-molecular-weight inhibitors or monoclonal antibodies represents a very promising personalized treatment strategy in pediatric oncology. In this study, we present the successful and clinically relevant use of commercially available phospho-protein arrays for analyses of the phosphorylation profiles of a broad spectrum of receptor tyrosine kinases and their downstream signaling proteins in tumor tissue samples. Although these arrays were made for research purposes on human biological samples, they have already been used by several authors to profile various tumor types. Our study performed a systematic analysis of the advantages and pitfalls of the use of this method for personalized clinical medicine. In certain clinical cases and their series, we demonstrated the important aspects of data processing and evaluation, the use of phospho-protein arrays for single sample and serial sample analyses, and the validation of obtained results by immunohistochemistry, as well as the possibilities of this method for the hierarchical clustering of pediatric solid tumors. Our results clearly show that phospho-protein arrays are apparently useful for the clinical consideration of druggable molecular targets within a specific tumor. Thus, their potential validation for diagnostic purposes may substantially improve the personalized approach in the treatment of relapsed or refractory solid tumors.
- Klíčová slova
- low-molecular-weight inhibitors, pediatric solid tumors, phospho-protein arrays, phosphorylation profiling, receptor tyrosin kinases, signal transduction,
- Publikační typ
- časopisecké články MeSH
Introduction: The individualization of treatment is attractive, especially in children with high-risk cancer. In such a rare and very heterogeneous group of diseases, large population-based clinical randomized trials are not feasible without international collaboration. We therefore propose comparative patient series analysis in a real-life scenario. Methods: Open cohort observational study, comparative analysis. Seventy patients with high-risk solid tumors diagnosed between 2003 and 2015 and in whom the treatment was individualized either empirically or based on biomarkers were analyzed. The heterogeneity of the cohort and repeated measurements were advantageously utilized to increase effective sample size using appropriate statistical tools. Results: We demonstrated a beneficial effect of empirically given low-dose metronomic chemotherapy (HR 0.46 for relapses, p = 0.017) as well as various repurposed or targeted agents (HR 0.15 for deaths, p = 0.004) in a real-life scenario. However, targeted agents given on the basis of limited biological information were not beneficial. Conclusions: Comparative patient series analysis provides institutional-level evidence for treatment individualization in high-risk pediatric malignancies. Our findings emphasize the need for a comprehensive, multi omics assessment of the tumor and the host as well whenever molecularly driven targeted therapies are being considered. Low-dose metronomic chemotherapy or local control of the disease may be a more rational option in situations where targeted treatment cannot be justified by robust evidence and comprehensive biological information. "Targeted drugs" may be given empirically with a realistic benefit expectation when based on robust rationale.
- Klíčová slova
- cancer, children, clinical trials, comparative effectiveness research, metronomic, personalized medicine, targeted therapy,
- Publikační typ
- časopisecké články MeSH
Infantile myofibromatosis represents one of the most common proliferative fibrous tumors of infancy and childhood. More effective treatment is needed for drug-resistant patients, and targeted therapy using specific protein kinase inhibitors could be a promising strategy. To date, several studies have confirmed a connection between the p.R561C mutation in gene encoding platelet-derived growth factor receptor beta (PDGFR-beta) and the development of infantile myofibromatosis. This study aimed to analyze the phosphorylation of important kinases in the NSTS-47 cell line derived from a tumor of a boy with infantile myofibromatosis who harbored the p.R561C mutation in PDGFR-beta. The second aim of this study was to investigate the effects of selected protein kinase inhibitors on cell signaling and the proliferative activity of NSTS-47 cells. We confirmed that this tumor cell line showed very high phosphorylation levels of PDGFR-beta, extracellular signal-regulated kinases (ERK) 1/2 and several other protein kinases. We also observed that PDGFR-beta phosphorylation in tumor cells is reduced by the receptor tyrosine kinase inhibitor sunitinib. In contrast, MAPK/ERK kinases (MEK) 1/2 and ERK1/2 kinases remained constitutively phosphorylated after treatment with sunitinib and other relevant protein kinase inhibitors. Our study showed that sunitinib is a very promising agent that affects the proliferation of tumor cells with a p.R561C mutation in PDGFR-beta.
- Klíčová slova
- FR180204, U0126, erlotinib, infantile myofibromatosis, platelet-derived growth factor receptor, protein kinase inhibitors, receptor tyrosine kinases, sunitinib, targeted therapy,
- MeSH
- butadieny aplikace a dávkování terapeutické užití MeSH
- dítě MeSH
- erlotinib aplikace a dávkování terapeutické užití MeSH
- fosforylace účinky léků MeSH
- inhibitory proteinkinas aplikace a dávkování terapeutické užití MeSH
- kojenec MeSH
- lidé MeSH
- mutace * MeSH
- myofibromatóza vrozené farmakoterapie genetika MeSH
- nádorové buněčné linie MeSH
- nitrily aplikace a dávkování terapeutické užití MeSH
- proliferace buněk účinky léků MeSH
- pyrazoly aplikace a dávkování terapeutické užití MeSH
- pyridaziny aplikace a dávkování terapeutické užití MeSH
- růstový faktor odvozený z trombocytů - receptor beta * genetika metabolismus MeSH
- sunitinib aplikace a dávkování terapeutické užití MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- butadieny MeSH
- erlotinib MeSH
- FR 180204 MeSH Prohlížeč
- inhibitory proteinkinas MeSH
- nitrily MeSH
- PDGFRB protein, human MeSH Prohlížeč
- pyrazoly MeSH
- pyridaziny MeSH
- růstový faktor odvozený z trombocytů - receptor beta * MeSH
- sunitinib MeSH
- U 0126 MeSH Prohlížeč
