Head and neck squamous cell carcinoma (HNSCC) is a disease with heterogeneous clinical behavior and response to therapies. Despite the introduction of multimodality treatment, 40–50% of patients with advanced disease recur. Therefore, there is an urgent need to improve the classification beyond the current parameters in clinical use to better stratify patients and the therapeutic approaches. Following a meta-analysis approach we built a large training set to whom we applied a Disease-Specific Genomic Analysis (DSGA) to identify the disease component embedded into the tumor data. Eleven independent microarray datasets were used as validation sets.Six different HNSCC subtypes that summarize the aberrant alterations occurring during tumor progression were identified. Based on their main biological characteristics and de-regulated signaling pathways, the subtypes were designed as immunoreactive, inflammatory, human papilloma virus (HPV)-like, classical, hypoxia associated, and mesenchymal. Our findings highlighted a more aggressive behavior for mesenchymal and hypoxia-associated subtypes. The Genomics Drug Sensitivity Project was used to identify potential associations with drug sensitivity and significant differences were observed among the six subtypes.To conclude, we report a robust molecularly defined subtype classification in HNSCC that can improve patient selection and pave the way to the development of appropriate therapeutic strategies.
Purpose: To identify the tumor portrait of the minority of head and neck squamous cell carcinoma (HNSCC) patients with recurrent-metastatic (RM) disease who upon treatment with platinum-based chemotherapy plus cetuximab present a long-lasting response.Experimental Design: The gene expression of pretreatment samples from 40 HNSCC-RM patients, divided in two groups [14 long-progression-free survival (PFS) and 26 short-PFS (median ¼ 19 and 3 months, respectively)], was associated with PFS and was challenged against a dataset from metastatic colon cancer patients treated with cetuximab. For biologic analysis, we performed functional and subtype association using gene set enrichment analysis, associated biology across all currently available HNSCC signatures, and inferred drug sensitivity using data from the Cancer Genomic Project.Results: The identified genomic profile exhibited a significant predictive value that was essentially confirmed in the single publicly available dataset of cetuximab-treated patients. The main divergence between long-and short-PFS groups was based on developmental/differentiation status. The long-PFS patients are characterized by basal subtype traits such as strong EGFR signaling phenotype and hypoxic differentiation, further validated by the significantly higher association with the hypoxia metagene. The short-PFS patients presented a strong activation of RAS signaling confirmed in an in vitro model of two isogenic HNSCC cell lines sensitive or resistant to cetuximab. The predicted drug sensitivity for all four EGFR inhibitors was higher in long-versus short-PFS patients (P range: <0.0022-1eÀ07).Conclusions: Our data uncover the biology behind response to platinum-based chemotherapy plus cetuximab in RM-HNSCC cancer and may have translational implications improving treatment selection.
Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cancer by incidence worldwide and considering the recent EUROCARE-5 population-based study the 5-year survival rate of HNSCC patients in Europe ranges between 69% in localized cases and 34% in patients with regional involvement. The development of high-throughput gene expression assays in the last two decades has provided the invaluable opportunity to improve our knowledge on cancer biology and to identify predictive signatures in the most deeply analyzed malignancies, such as hematological and breast cancers. At variance, till 2010, the number of reliable reports referring gene expression data related to HSNCC biology and prediction was quite limited. A critical revision of the literature reporting gene expression data in HNSCC indicated that in the last 6 years, there were new important studies with a relevant increase in the sample size and a more accurate selection of cases, the publication of a growing number of studies applying a computational integration (meta-analysis) of different microarray datasets addressing similar clinical/biological questions, the increased use of molecular sub-classification of tumors according to their gene expression, and the release of the publicly available largest dataset in HNSCC by The Cancer Genome Atlas (TCGA) consortium. Overall, also for this disease, it become evident that the expression analysis of the entire transcriptome has been enabling to achieve the identification of promising molecular signatures for (i) disclosure of the biology behind carcinogenesis with special focus on the HPV-related one, (ii) prediction of tumor recurrence or metastasis development, (iii) identification of subgroups of tumors with different biology and associated prognosis, and (iv) prediction of outcome and/or response to therapy. The increasing awareness of the relevance of strict collaboration among clinicians and translational researchers would in a near future enable the application of a personalized HNSCCs patients' treatment in the clinical practice based also on gene expression signatures.
This paper documents the process by which we, through gene and miRNA expression profiling of the same samples of head and neck squamous cell carcinomas (HNSCC) and an integrative miRNA-mRNA expression analysis, were able to identify candidate biomarkers of progression-free survival (PFS) in patients treated with cetuximab-based approaches. Through sparse partial least square–discriminant analysis (sPLS-DA) and supervised analysis, 36 miRNAs were identified in two components that clearly separated long- and short-PFS patients. Gene set enrichment analysis identified a significant correlation between the miRNA first-component and EGFR signaling, keratinocyte differentiation, and p53. Another significant correlation was identified between the second component and RAS, NOTCH, immune/inflammatory response, epithelial–mesenchymal transition (EMT), and angiogenesis pathways. Regularized canonical correlation analysis of sPLS-DA miRNA and gene data combined with the MAGIA2 web-tool highlighted 16 miRNAs and 84 genes that were interconnected in a total of 245 interactions. After feature selection by a smoothed t-statistic support vector machine, we identified three miRNAs and five genes in the miRNA-gene network whose expression result was the most relevant in predicting PFS (Area Under the Curve, AUC = 0.992). Overall, using a well-defined clinical setting and up-to-date bioinformatics tools, we are able to give the proof of principle that an integrative miRNA-mRNA expression could greatly contribute to the refinement of the biology behind a predictive model.
Despite impressive treatment advances, few options for refractory or relapsed Hodgkin Lymphoma (HL) are available and there is a need for new compounds development. A number of promising agents with multiple mechanisms of action are under investigation. Microenvironment and neoangiogenesis are acquiring a rising relevance in the pathophysiology and progression of HL. Everolimus (RAD001) is an oral antineoplastic agent derived from rapamycin, a macrocyclic lactone antibiotic, targeting the mammalian target of rapamycin (mTOR). Although the importance of mTOR signaling in the deregulated cell growth of human neoplastic cells has been recognized, this pathway is also emerging as a key regulator of the tumor response to hypoxia, as well as endothelial and stromal cells function, thereby regulating neoangiogenesis. Furthermore, mTOR plays an important role in anticancer drug resistance. The actions of everolimus within the mTOR pathway in HL result in decreased protein synthesis and cell cycle arrest, as well as in decreased angiogenesis. Everolimus has shown preliminary evidence of efficacy as a single-agent in heavily pretreated relapsed/refractory HL, with an overall fair safety profile. The purpose of this review is to discuss the employment of everolimus as an antiproliferative and antiangiogenic agent in HL and to report the critical role of the mTOR pathway and angiogenesis in this malignancy.
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