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1.
Cancer Med ; 4(5): 699-712, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25619980

RESUMO

Head and neck squamous cell carcinoma (HNSCC) remains a challenging cancer to treat with overall 5-year survival on the order of 50-60%. Therefore, predictive biomarkers for this disease would be valuable to provide more effective and individualized therapeutic approaches for these patients. While prognostic biomarkers such as p16 expression correlate with outcome; to date, no predictive biomarkers have been clinically validated for HNSCC. We generated xenografts in immunocompromised mice from six established HNSCC cell lines and evaluated response to cisplatin, cetuximab, and radiation. Tissue microarrays were constructed from pre- and posttreatment tumor samples derived from each xenograft experiment. Quantitative immunohistochemistry was performed using a semiautomated imaging and analysis platform to determine the relative expression of five potential predictive biomarkers: epidermal growth factor receptor (EGFR), phospho-EGFR, phospho-Akt, phospho-ERK, and excision repair cross-complementation group 1 (ERCC1). Biomarker levels were compared between xenografts that were sensitive versus resistant to a specific therapy utilizing a two-sample t-test with equal standard deviations. Indeed the xenografts displayed heterogeneous responses to each treatment, and we linked a number of baseline biomarker levels to response. This included low ERCC1 being associated with cisplatin sensitivity, low phospho-Akt correlated with cetuximab sensitivity, and high total EGFR was related to radiation resistance. Overall, we developed a systematic approach to identifying predictive biomarkers and demonstrated several connections between biomarker levels and treatment response. Despite these promising initial results, this work requires additional preclinical validation, likely involving the use of patient-derived xenografts, prior to moving into the clinical realm for confirmation among patients with HNSCC.


Assuntos
Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/mortalidade , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Biomarcadores , Linhagem Celular Tumoral , Cetuximab/administração & dosagem , Cetuximab/farmacologia , Cisplatino/administração & dosagem , Cisplatino/farmacologia , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Endonucleases/metabolismo , Receptores ErbB/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/terapia , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Imuno-Histoquímica , Camundongos , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Radioterapia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Cancer Res ; 73(15): 4791-800, 2013 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-23749640

RESUMO

Patients with human papillomavirus (HPV+)-associated head and neck cancer (HNC) show significantly improved survival outcome compared with those with HPV-negative (HPV-) tumors. Published data examining this difference offers conflicting results to date. We systematically investigated the radiation sensitivity of all available validated HPV+ HNC cell lines and a series of HPV- HNC cell lines using in vitro and in vivo techniques. HPV+ HNCs exhibited greater intrinsic radiation sensitivity (average SF2 HPV-: 0.59 vs. HPV+: 0.22; P < 0.0001), corresponding with a prolonged G2-M cell-cycle arrest and increased apoptosis following radiation exposure (percent change 0% vs. 85%; P = 0.002). A genome-wide microarray was used to compare gene expression 24 hours following radiation between HPV+ and HPV- cell lines. Multiple genes in TP53 pathway were upregulated in HPV+ cells (Z score 4.90), including a 4.6-fold increase in TP53 (P < 0.0001). Using immortalized human tonsillar epithelial (HTE) cells, increased radiation sensitivity was seen in cell expressing HPV-16 E6 despite the effect of E6 to degrade p53. This suggested that low levels of normally functioning p53 in HPV+ HNC cells could be activated by radiation, leading to cell death. Consistent with this, more complete knockdown of TP53 by siRNA resulted in radiation resistance. These results provide clear evidence, and a supporting mechanism, for increased radiation sensitivity in HPV+ HNC relative to HPV- HNC. This issue is under active investigation in a series of clinical trials attempting to de-escalate radiation (and chemotherapy) in selected patients with HPV+ HNC in light of their favorable overall survival outcome.


Assuntos
Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/virologia , Infecções por Papillomavirus/complicações , Tolerância a Radiação/fisiologia , Proteína Supressora de Tumor p53/biossíntese , Animais , Apoptose/fisiologia , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Feminino , Humanos , Immunoblotting , Camundongos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcriptoma , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Clin Cancer Res ; 19(4): 855-64, 2013 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-23251001

RESUMO

PURPOSE: To develop a clinically relevant model system to study head and neck squamous cell carcinoma (HNSCC), we have established and characterized a direct-from-patient tumorgraft model of human papillomavirus (HPV)-positive and HPV-negative cancers. EXPERIMENTAL DESIGN: Patients with newly diagnosed or recurrent HNSCC were consented for donation of tumor specimens. Surgically obtained tissue was implanted subcutaneously into immunodeficient mice. During subsequent passages, both formalin-fixed/paraffin-embedded as well as flash-frozen tissues were harvested. Tumors were analyzed for a variety of relevant tumor markers. Tumor growth rates and response to radiation, cisplatin, or cetuximab were assessed and early passage cell strains were developed for rapid testing of drug sensitivity. RESULTS: Tumorgrafts have been established in 22 of 26 patients to date. Significant diversity in tumorgraft tumor differentiation was observed with good agreement in degree of differentiation between patient tumor and tumorgraft (Kappa 0.72). Six tumorgrafts were HPV-positive on the basis of p16 staining. A strong inverse correlation between tumorgraft p16 and p53 or Rb was identified (Spearman correlations P = 0.085 and P = 0.002, respectively). Significant growth inhibition of representative tumorgrafts was shown with cisplatin, cetuximab, or radiation treatment delivered over a two-week period. Early passage cell strains showed high consistency in response to cancer therapy between tumorgraft and cell strain. CONCLUSIONS: We have established a robust human tumorgraft model system for investigating HPV-positive and HPV-negative HNSCC. These tumorgrafts show strong correlation with the original tumor specimens and provide a powerful resource for investigating mechanisms of therapeutic response as well as preclinical testing.


Assuntos
Carcinoma de Células Escamosas/virologia , Transformação Celular Neoplásica/genética , Neoplasias de Cabeça e Pescoço/virologia , Papillomaviridae/patogenicidade , Animais , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/radioterapia , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/patologia , Cisplatino/administração & dosagem , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Camundongos , Papillomaviridae/efeitos dos fármacos , Papillomaviridae/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço , Transplante Heterólogo
4.
Sensors (Basel) ; 12(4): 5159-69, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22666080

RESUMO

Over the last 10 years, it has become clear that patients with head and neck cancer can be stratified into two distinct subgroups on the basis of the etiology of their disease. Patients with human papillomavirus-related cancers have significantly better survival rates and may necessitate different therapeutic approaches than those with tobacco and/or alcohol related cancers. This review discusses the various biomarkers currently in use for identification of patients with HPV-positive cancers with a focus on the advantages and limitations of molecular and nano-scale markers.


Assuntos
Neoplasias de Cabeça e Pescoço/virologia , Papillomaviridae/isolamento & purificação , Infecções Tumorais por Vírus/virologia , Southern Blotting , Humanos , Imuno-Histoquímica , Hibridização In Situ , Reação em Cadeia da Polimerase , Prognóstico
5.
Plast Reconstr Surg ; 125(3): 989-94, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20195124

RESUMO

BACKGROUND: Current rates of postoperative nausea and vomiting experienced by outpatient surgery patients are as high as 20 to 30 percent. Electroacustimulation therapy has been demonstrated to be effective in controlling these symptoms, but trials identifying its efficacy in the outpatient surgery population are lacking. METHODS: One hundred twenty-two patients undergoing surgical procedures at an outpatient surgery center were randomized to two treatment arms. The first arm received the standardized pharmacologic postoperative nausea and vomiting prevention typical for patients undergoing outpatient surgery, whereas in the second arm, the ReliefBand and pharmacologic measures were used. The ReliefBand is a U.S. Food and Drug Administration-approved electroacustimulation device. Electroacustimulation is a derivative of acupuncture therapy that uses a small electrical current to stimulate acupuncture points on the human body and is thought to relieve nausea, vomiting, and pain. Outcomes measured were pain and nausea symptoms, emetic events, the need for rescue medications, and the time to discharge. RESULTS: The electroacustimulation arm reported statistically significant lower nausea scores at 30 minutes and 120 minutes postoperatively (p < 0.05). In addition, subgroup analysis demonstrated significant findings in favor of the experimental group, with anatomical subsets of surgical patients requiring less pain medication and shorter times from surgery to discharge when compared with the standard treatment. However, electroacustimulation did not have a significant effect on the amount of pain experienced by patients in any group. CONCLUSION: The authors' study demonstrates that electroacustimulation offers added protection against symptoms of postoperative nausea and vomiting in an outpatient cosmetic surgery population, representing a safe and cost-effective addition to current pharmacologic preventive measures.


Assuntos
Terapia por Acupuntura/métodos , Procedimentos de Cirurgia Plástica , Náusea e Vômito Pós-Operatórios/prevenção & controle , Pontos de Acupuntura , Humanos , Mamoplastia , Ambulatório Hospitalar , Dor Pós-Operatória/prevenção & controle , Estudos Prospectivos , Rinoplastia
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