RESUMO
To improve treatment outcomes in non-small cell lung cancer (NSCLC), preclinical models that can better predict individual patient response to novel therapies are urgently needed. Using freshly resected tumor tissue, we describe an optimized ex vivo explant culture model that enables concurrent evaluation of NSCLC response to therapy while maintaining the tumor microenvironment. We found that approximately 70% of primary NSCLC specimens were amenable to explant culture with tissue integrity intact for up to 72 hours. Variations in cisplatin sensitivity were noted with approximately 50% of cases responding ex vivo Notably, explant responses to cisplatin correlated significantly with patient survival (P = 0.006) irrespective of tumor stage. In explant tissue, cisplatin-resistant tumors excluded platinum ions from tumor areas in contrast to cisplatin-sensitive tumors. Intact TP53 did not predict cisplatin sensitivity, but a positive correlation was observed between cisplatin sensitivity and TP53 mutation status (P = 0.003). Treatment of NSCLC explants with the targeted agent TRAIL revealed differential sensitivity with the majority of tumors resistant to single-agent or cisplatin combination therapy. Overall, our results validated a rapid, reproducible, and low-cost platform for assessing drug responses in patient tumors ex vivo, thereby enabling preclinical testing of novel drugs and helping stratify patients using biomarker evaluation. Cancer Res; 77(8); 2029-39. ©2017 AACR.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Cisplatino/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Cisplatino/farmacocinética , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Técnicas de Cultura de Tecidos/métodos , Proteína Supressora de Tumor p53/biossíntese , Proteína Supressora de Tumor p53/genéticaRESUMO
The malignant phenotype is largely the consequence of dysregulated gene expression. Transformed cells depend upon not just a global increase in protein synthesis but an altered translational landscape in which pro-oncogenic mRNAs are translationally up-regulated. Such mRNAs have been shown to possess longer and more structured 5'-UTRs requiring high levels of eukaryotic initiation factor 4A (eIF4A) helicase activity for efficient translation. As such there is a developing focus on targeting eIF4A as a cancer therapy. In order for such treatments to be successful, we must develop a detailed understanding of the mechanisms which make specific mRNAs more dependent on eIF4A activity than others. It is also crucial to fully characterize the potentially distinct roles of eIF4A1 and eIF4A2, which until recently were thought to be functionally interchangeable. This review will highlight the recent advances made in this field that address these issues.
Assuntos
Fator de Iniciação 4A em Eucariotos/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Biossíntese de Proteínas/genética , Compostos de Epóxi/uso terapêutico , Fator de Iniciação 4A em Eucariotos/antagonistas & inibidores , Fator de Iniciação 4A em Eucariotos/metabolismo , Humanos , Macrolídeos/uso terapêutico , Terapia de Alvo Molecular/métodos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Esteróis/uso terapêutico , Tiazóis/uso terapêutico , Triterpenos/uso terapêuticoRESUMO
Micro-RNAs (miRNAs) are frequently dysregulated in a range of human malignancies, many have been shown to act either as tumour supressors or oncogenes and several have been implicated in breast cancer. However, breast cancer is a diverse disease and little is known about the relationships between miRNA expression, clinical outcome and tumour subtype. We used locked nucleic acid probe in situ hybridization (LNA-ISH) to visualize, in tissue micro-arrays (TMAs) of 2919 formalin-fixed paraffin-embedded (FFPE) archival breast tumours, the expression of two key miRNAs that are frequently lost in a range of solid malignancies, let-7b and miR-205. These miRNAs were also quantified by quantitative reverse transcription PCR in cores of FFPE tissue from 40 of these cases, demonstrating that LNA-ISH is semi-quantitative. The tumours in the TMAs were assigned to subtypes based on their immunohistochemical (IHC) staining with ER, PR, HER2, CK5/6 and EGFR. let-7b expression was shown to be associated with luminal tumours and to have an independent significant positive prognostic value in this group. miR-205 is associated with tumours of ductal morphology and is of significant positive prognostic value within these tumours. We propose that the expression of miR-205 may contribute to ductal tumour morphology.
