RESUMEN

Recent clinical research has provided evidence that cancer progression and therapy resistance is driven not only by tumor's genetic profile but also by complex paracrine interactions within the tumor microenvironment (TME). The role of TME in modulating tumor drug sensitivity is increasingly recognized and targeting TME has been the focus of novel therapeutic approaches. Two recent reports show that a new anti-cancer drug, the inhibitor NT157 has the potential to inhibit IGF-1R and STAT3 signaling pathways in cancer cells and stroma cells of TME leading to a decrease in cancer cell survival.

Asunto(s)

Antineoplásicos/farmacología , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Pirogalol/análogos & derivados , Células del Estroma/efectos de los fármacos , Sulfonamidas/farmacología , Antineoplásicos/uso terapéutico , Humanos , Terapia Molecular Dirigida , Pirogalol/farmacología , Pirogalol/uso terapéutico , Sulfonamidas/uso terapéutico , Microambiente Tumoral/efectos de los fármacos

RESUMEN

BACKGROUND: Squamous cell carcinoma of the head and neck (SCCHN) was traditionally associated with smoking and alcohol use; however, human papillomavirus (HPV) infection has recently been implicated as a novel risk factor for oropharyngeal tumors. Furthermore, HPV-associated oropharyngeal carcinoma (OPC) appears to be a distinct entity with different epidemiology, biology, and clinical outcomes. METHODS: Here, we comprehensively review the existing data regarding HPV status and prognostic or predictive outcomes in both the locoregionally advanced (LA) and recurrent/metastatic (RM) disease setting and discuss ongoing trials that may eventually impact the treatment of patients with HPV-positive (HPV+) SCCHN. RESULTS: A body of retrospective and prospective data established an association between HPV+ OPC and better survival, particularly for LA disease. Current data on RM disease are limited, but they also suggest prognostic significance for HPV. CONCLUSIONS: Better outcomes in HPV+ LA disease may allow for less aggressive treatment in the future, and several trials are evaluating deintensified regimens in patients with HPV+, LA OPC; it should be emphasized that deintensification strategies are appropriate only in a clinical research setting and only for selected subgroups of HPV+ patients. In addition, HPV-targeted strategies, such as vaccines, are currently undergoing clinical evaluation. On the other hand, the prognostic impact of HPV in RM disease requires further validation before any modifications in treatment can be made. Likewise, the predictive significance of HPV status in both disease settings remains to be defined. CLINICAL TRIAL NUMBERS: NCT00226239, NCT00301028, NCT00387127, NCT00410826, NCT00503997, NCT00514943, NCT00544414, NCT00768664, NCT00939627, NCT01084083, NCT01302834, NCT01687413, NCT01706939.

Asunto(s)

Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias Orofaríngeas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/virología , Cetuximab , Ensayos Clínicos como Asunto , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/virología , Humanos , Neoplasias Orofaríngeas/patología , Neoplasias Orofaríngeas/virología , Panitumumab , Papillomaviridae/patogenicidad , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Carcinoma de Células Escamosas de Cabeza y Cuello

RESUMEN

Squamous-cell cancer of the head and neck (SCCHN) represents a heterogeneous disease entity, with various etiological factors implicated in the genesis of distinct molecular subsets of tumors, which exhibit different biological and clinical behavior. Treatment of SCCHN is expected to change in the next decade as targeted therapies continue to make strides. Recently, next-generation sequencing studies conducted on ∼190 SCCHN specimens shed light into the molecular pathogenesis of the disease. These studies discovered mutations in genes involved in the differentiation program of squamous epithelium and the Notch/p63 axis (such as NOTCH1, TP63 and FBXW7), and validated genetic alterations derived from previous studies (such as mutations in TP53, CDKN2A, PIK3CA, CCND1 and HRAS) as driver genetic events in SCCHN neoplastic transformation. More recently, comprehensive data from The Cancer Genome Atlas (TCGA) project on 306 SCCHN specimens provided further insight into SCCHN inherent molecular complexity, identifying novel significantly mutated genes, including FAT1, MLL2, TGFRBR2, HLA-A, NFE2l2 and CASP8. In this article, we provide an overview of the mutational spectrum of SCCHN, with emphasis on the clinical implementation of this knowledge. We also discuss the potential integration of new data within the framework of precision cancer medicine.

Asunto(s)

Carcinogénesis/genética , Carcinoma de Células Escamosas/genética , Neoplasias de Cabeza y Cuello/genética , Mutación , Proteínas de Neoplasias/genética , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Diferenciación Celular/genética , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/patología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Terapia Molecular Dirigida , Patología Molecular , Análisis de Secuencia de ADN , Carcinoma de Células Escamosas de Cabeza y Cuello

RESUMEN

PURPOSE: Cetuximab, an antibody directed against the EGF receptor, is an effective clinical therapy for patients with head and neck squamous cell cancer (HNSCC). Despite great clinical promise, intrinsic or acquired cetuximab resistance hinders successful treatment outcomes but little is known about the underlying mechanism. EXPERIMENTAL DESIGN: To study the role of oncogenic HRAS in cetuximab resistance in HNSCC, the frequency of oncogenic HRAS mutations was determined in a cohort of 180 genomic DNAs from head and neck cancer specimens. We also used a combination of cetuximab-resistant cell lines and a transgenic mouse model of RAS-driven oral cancer to identify an oncogenic RAS-specific gene expression signature that promotes cetuximab resistance. RESULTS: Here, we show that activation of RAS signaling leads to persistent extracellular signal-regulated kinase 1/2 signaling and consequently to cetuximab resistance. HRAS depletion in cells containing oncogenic HRAS or PIK3CA restored cetuximab sensitivity. In our study, the gene expression signature of c-MYC, BCL-2, BCL-XL, and cyclin D1 upon activation of MAPK signaling was not altered by cetuximab treatment, suggesting that this signature may have a pivotal role in cetuximab resistance of RAS-activated HNSCC. Finally, a subset of patients with head and neck cancer with oncogenic HRAS mutations was found to exhibit de novo resistance to cetuximab-based therapy. CONCLUSIONS: Collectively, these findings identify a distinct cetuximab resistance mechanism. Oncogenic HRAS in HNSCC promotes activation of ERK signaling, which in turn mediates cetuximab resistance through a specific gene expression signature. Clin Cancer Res; 20(11); 2933-46. ©2014 AACR.

Asunto(s)

Carcinoma de Células Escamosas/genética , Resistencia a Antineoplásicos/genética , Neoplasias de Cabeza y Cuello/genética , Sistema de Señalización de MAP Quinasas/fisiología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas ras/genética , Animales , Anticuerpos Monoclonales Humanizados/farmacología , Antineoplásicos/farmacología , Western Blotting , Carcinoma de Células Escamosas/metabolismo , Cetuximab , Técnicas de Sustitución del Gen , Neoplasias de Cabeza y Cuello/metabolismo , Humanos , Ratones , Ratones Transgénicos , Microscopía Confocal , Mutación , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor Cross-Talk/fisiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Carcinoma de Células Escamosas de Cabeza y Cuello , Transcriptoma , Proteínas ras/metabolismo

RESUMEN

BACKGROUND: We sought to determine biomarker expression differences in head and neck squamous cell cancers (HNSCCs) based on p16/human papillomavirus (HPV) classification. In addition, our aim was to explore how expression of biomarkers is modulated after E6/E7 repression in HPV16⁺ oropharyngeal cancer cells. METHODS: HPV16⁺ and HPV⁻ HNSCC cells were infected with retroviruses expressing short hairpin RNA targeting HPV16 E6/E7. Components of the epidermal growth factor receptor (EGFR) pathway before and after E6/E7 gene silencing were analyzed by immunoblotting and qRT-PCR. Protein expression of 13 biomarkers was analyzed using AQUA on a tissue microarray (TMA). The HPV16 status was determined using HPV16 in situ hybridization (ISH). RESULTS: In HPV16⁺ cells, E6/E7 silencing was associated with PTEN upregulation and reduction of phosphorylated EGFR. Tumors were classified into four categories based on the HPV and p16 status. HPV⁺/p16⁺ tumors expressed significantly higher levels of E-cadherin (P = 0.003), PTEN (P = 0.004), lower levels of PI3Kp110 and ß-catenin (P = 0.07). There was a significant difference in overall survival (OS, P = 0.016) among the four subsets. The median OS was 24.83 months for p16⁻/HPV⁻ patients, 11.63 for p16⁻/HPV⁺ patients and was not reached for p16⁺/HPV⁻ and p16⁺/HPV⁺ groups. CONCLUSIONS: Aberrant EGFR signaling contributes to malignant conversion of HPV16⁺ HNSCC cells. These results validate ß-catenin as a distinct biomarker in HPV⁺/p16⁺ HNSCC. Wnt signaling inhibitors merit exploration in HPV⁺/p16⁺ HNSCC.

Asunto(s)

Carcinoma de Células Escamosas/metabolismo , Receptores ErbB/metabolismo , Neoplasias de Cabeza y Cuello/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Orofaríngeas/metabolismo , beta Catenina/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/virología , Línea Celular Tumoral , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Receptores ErbB/genética , Femenino , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/virología , Humanos , Masculino , Proteínas Oncogénicas Virales/genética , Proteínas Oncogénicas Virales/metabolismo , Neoplasias Orofaríngeas/genética , Neoplasias Orofaríngeas/virología , Fosfohidrolasa PTEN/biosíntesis , Proteínas E7 de Papillomavirus/genética , Proteínas E7 de Papillomavirus/metabolismo , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/genética , Infecciones por Papillomavirus/virología , Fosforilación , Interferencia de ARN , ARN Interferente Pequeño , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello , Proteína p53 Supresora de Tumor/metabolismo , Vía de Señalización Wnt

RESUMEN

Two overlapping clones encoding for a ribonuclease from six-day-old larvae of the insect Ceratitis capitata (Cc-RNase) have been isolated by immunoscreening a cDNA library and by 5' RACE. The sequence of the Cc-RNase cDNA contains an open reading frame of 414 nucleotides encoding for a precursor protein of 138 amino acids long with a putative signal peptide consisting of 19 amino acids. The calculated M(r) of the mature protein was found to be 13.7 kDa. Multiple alignments of the deduced amino acid Cc-RNase sequence with other ribonucleases revealed an approximate 25% average identity. Despite the low percentage of identity, histidine and lysine residues which are essential for its catalytic activity, were found to be completely conserved. Furthermore, expression of the clone in E. coli resulted in the production of a recombinant product that showed strong immunoreactivity with anti-RNase specific antibodies. These results support the hypothesis that the identified clone encodes for a protein which is a new member of the RNase superfamily.

Asunto(s)

ADN Complementario/genética , ADN Complementario/aislamiento & purificación , Dípteros/enzimología , Dípteros/genética , Ribonucleasas/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Clonación Molecular , Cartilla de ADN/genética , Escherichia coli/genética , Genes de Insecto , Larva/enzimología , Datos de Secuencia Molecular , ARN Mensajero/genética , ARN Mensajero/metabolismo , Homología de Secuencia de Aminoácido