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1.
Head Neck ; 44(5): 1192-1205, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35224804

RESUMO

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a debilitating disease with poor survival. Although epidermal growth factor receptor (EGFR)-targeting antibody cetuximab improves survival in some settings, responses are limited suggesting that alternative approaches are needed. METHODS: We performed a high throughput drug screen to identify EGFR inhibitor-based synergistic combinations of clinically advanced inhibitors in models resistant to EGFR inhibitor monotherapies, and then performed downstream validation experiments on prioritized synergistic combinations. RESULTS: From our screen, we re-discovered known synergistic EGFR inhibitor combinations with FGFR or IGF-1R inhibitors that were broadly effective and also discovered novel synergistic combinations with XIAP inhibitor and DNMT inhibitors that were effective in only a subset of models. CONCLUSIONS: Conceptually, our data identify novel synergistic combinations that warrant evaluation in future studies, and suggest that some combinations, although highly synergistic, will require parallel companion diagnostic development to be effectively advanced in patients.


Assuntos
Antineoplásicos , Neoplasias de Cabeça e Pescoço , Carcinoma de Células Escamosas de Cabeça e Pescoço , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Cetuximab/farmacologia , Cetuximab/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico
2.
BMC Cancer ; 21(1): 636, 2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34051734

RESUMO

BACKGROUND: Sinonasal Undifferentiated Carcinoma (SNUC) is a rare and aggressive skull base tumor with poor survival and limited treatment options. To date, targeted sequencing studies have identified IDH2 and SMARCB1 as potential driver alterations, but the molecular alterations found in SMARCB1 wild type tumors are unknown. METHODS: We evaluated survival outcomes in a cohort of 46 SNUC patients treated at an NCI designated cancer center and identify clinical and disease variables associated with survival on Kaplan-Meier and Cox multivariate survival analysis. We performed exome sequencing to characterize a series of SNUC tumors (n = 5) and cell line (MDA8788-6) to identify high confidence mutations, copy number alterations, microsatellite instability, and fusions. Knockdown studies using siRNA were utilized for validation of a novel PGAP3-SRPK1 gene fusion. RESULTS: Overall survival analysis revealed no significant difference in outcomes between patients treated with surgery +/- CRT and CRT alone. Tobacco use was the only significant predictor of survival. We also confirmed previously published findings on IDH and SMARC family mutations and identified novel recurrent aberrations in the JAK/STAT and PI3K pathways. We also validated a novel PGAP3-SRPK1 gene fusion in the SNUC cell line, and show that knockdown of the fusion is negatively associated with EGFR, E2F and MYC signaling. CONCLUSION: Collectively, these data demonstrate recurrent alterations in the SWI/SNF family as well as IDH, JAK/STAT, and PI3K pathways and discover a novel fusion gene (PGAP3-SRPK1). These data aim to improve understanding of possible driver mutations and guide future therapeutic strategies for this disease.


Assuntos
Hidrolases de Éster Carboxílico/genética , Carcinoma/genética , Neoplasias do Seio Maxilar/genética , Recidiva Local de Neoplasia/epidemiologia , Proteínas de Fusão Oncogênica/genética , Proteínas Serina-Treonina Quinases/genética , Receptores de Superfície Celular/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/mortalidade , Carcinoma/terapia , Linhagem Celular Tumoral , Quimiorradioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Seguimentos , Técnicas de Silenciamento de Genes , Humanos , Estimativa de Kaplan-Meier , Masculino , Neoplasias do Seio Maxilar/mortalidade , Neoplasias do Seio Maxilar/terapia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Estudos Retrospectivos , Adulto Jovem
3.
Head Neck ; 41(9): 3114-3124, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31090975

RESUMO

BACKGROUND: Laryngeal squamous cell carcinomas (LSCCs) have a high risk of recurrence and poor prognosis. Patient-derived cancer cell lines remain important preclinical models for advancement of new therapeutic strategies, and comprehensive characterization of these models is vital in the precision medicine era. METHODS: We performed exome and transcriptome sequencing as well as copy number analysis of a panel of LSCC-derived cell lines that were established at the University of Michigan and are used in laboratories worldwide. RESULTS: We observed a complex array of alterations consistent with those reported in The Cancer Genome Atlas head and neck squamous cell carcinoma project, including aberrations in PIK3CA, EGFR, CDKN2A, TP53, and NOTCH family and FAT1 genes. A detailed analysis of FAT family genes and associated pathways showed disruptions to these genes in most cell lines. CONCLUSIONS: The molecular profiles we have generated indicate that as a whole, this panel recapitulates the molecular diversity observed in patients and will serve as useful guides in selecting cell lines for preclinical modeling.


Assuntos
Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Sequenciamento do Exoma , Neoplasias Laríngeas/genética , Mutação , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transcriptoma
4.
Oral Oncol ; 87: 144-151, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30527230

RESUMO

OBJECTIVES: We sought to describe the genetic complexity of 14 UM-SCC oral cavity cancer cell lines that have remained uncharacterized despite being used as model systems for decades. MATERIALS AND METHODS: We performed exome sequencing on 14 oral cavity UM-SCC cell lines and denote the mutational profile of each line. We used a SNP array to profile the multiple copy number variations of each cell line and use immunoblotting to compare alterations to protein expression of commonly amplified genes (EGFR, PIK3CA, etc.). RNA sequencing was performed to characterize the expression of genes with copy number alterations. RESULTS: The cell lines displayed a highly complex network of genetic aberrations that was consistent with alterations identified in the HNSCC TCGA project including PIK3CA amplification, CDKN2A deletion, as well as TP53 and CASP8 mutations, enabling genetic stratification of each cell line in the panel. Copy number FISH and spectral karyotyping analysis demonstrate that cell lines retain chromosomal heterogeneity. CONCLUSIONS: Collectively, we developed an important resource for future oral cavity HNSCC cell line studies and highlight the complexity of genomic aberrations in cell lines.


Assuntos
Neoplasias Bucais/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Caspase 8/genética , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Variações do Número de Cópias de DNA , Humanos , Cariotipagem , Neoplasias Bucais/patologia , Mutação , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Proteína Supressora de Tumor p53/genética , Sequenciamento do Exoma
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