RESUMO
PIK3CA is the most commonly altered oncogene in head and neck squamous cell carcinoma (HNSCC). We evaluated the impact of nonsteroidal anti-inflammatory drugs (NSAIDs) on survival in a PIK3CA-characterized cohort of 266 HNSCC patients and explored the mechanism in relevant preclinical models including patient-derived xenografts. Among subjects with PIK3CA mutations or amplification, regular NSAID use (≥6 mo) conferred markedly prolonged disease-specific survival (DSS; hazard ratio 0.23, P = 0.0032, 95% CI 0.09-0.62) and overall survival (OS; hazard ratio 0.31, P = 0.0043, 95% CI 0.14-0.69) compared with nonregular NSAID users. For PIK3CA-altered HNSCC, predicted 5-yr DSS was 72% for NSAID users and 25% for nonusers; predicted 5-yr OS was 78% for regular NSAID users and 45% for nonregular users. PIK3CA mutation predicted sensitivity to NSAIDs in preclinical models in association with increased systemic PGE2 production. These findings uncover a biologically plausible rationale to implement NSAID therapy in PIK3CA-altered HNSCC.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Carcinoma de Células Escamosas , Classe I de Fosfatidilinositol 3-Quinases , Neoplasias de Cabeça e Pescoço , Mutação , Proteínas de Neoplasias , Adulto , Idoso , Animais , Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/terapia , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Intervalo Livre de Doença , Feminino , Neoplasias de Cabeça e Pescoço/enzimologia , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Taxa de Sobrevida , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: To test whether a clinical algorithm using routine cytological molecular testing (MT) promotes initial total thyroidectomy (TT) for clinically significant thyroid cancer (sTC) and/or correctly limits surgery to lobectomy when appropriate. BACKGROUND: Either TT or lobectomy is often needed to diagnose differentiated thyroid cancer. Determining the correct extent of initial thyroidectomy is challenging. METHODS: After implementing an algorithm for prospective MT of in-house fine-needle aspiration biopsy specimens, we conducted a single-institution cohort study of all patients (N = 671) with nonmalignant cytology who had thyroidectomy between October 2010 and March 2012, cytological diagnosis using 2008 Bethesda criteria, and 1 or more indications for thyroidectomy by 2009 American Thyroid Association guidelines. sTC was defined by histological differentiated thyroid cancer of 1 cm or more and/or lymph node metastasis. Cohort 2 patients did not have MT or had unevaluable results. In cohort 1, MT for a multigene mutation panel was performed for nonbenign cytology, and positive MT results indicated initial TT. RESULTS: MT guidance was associated with a higher incidence of sTC after TT (P = 0.006) and a lower rate of sTC after lobectomy (P = 0.03). Without MT results, patients with indeterminate (follicular lesion of undetermined significance/follicular or oncocytic neoplasm) cytology who received initial lobectomy were 2.5 times more likely to require 2-stage surgery for histological sTC (P < 0.001). In the 501 patients with non-sTC for whom lobectomy was the appropriate extent of surgery, lobectomy was correctly performed more often with routine preoperative MT (P = 0.001). CONCLUSIONS: Fine-needle aspiration biopsy MT for BRAF, RAS, PAX8-PPARγ, and RET-PTC expedites optimal initial surgery for differentiated thyroid cancer, facilitating succinct definitive management for patients with thyroid nodules.
Assuntos
Algoritmos , Biópsia por Agulha Fina/métodos , Guias de Prática Clínica como Assunto , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/patologia , Tireoidectomia/métodos , Diagnóstico Diferencial , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estudos Retrospectivos , Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/cirurgia , Nódulo da Glândula Tireoide/cirurgiaRESUMO
Smokers experience aberrant gene promoter methylation in their bronchial cells, which may predispose to the development of neoplasia. Hydralazine is a DNA demethylating agent, and valproic acid is a histone deacetylase inhibitor, and both have modest but synergistic anticancer activity in vitro. We conducted a phase I trial combining valproic acid and hydralazine to determine the maximally tolerated dose (MTD) of hydralazine in combination with a therapeutic dose of valproic acid in patients with advanced, unresectable, and previously treated solid cancers. Twenty females and nine males were enrolled, with a median age of 57 years and a median ECOG performance status of 0. Grade 1 lymphopenia and fatigue were the most common adverse effects. Three subjects withdrew for treatment-related toxicities occurring after the DLT observation period, including testicular edema, rash, and an increase in serum lipase accompanied by hyponatremia in one subject each. A true MTD of hydralazine in combination with therapeutic doses of valproic acid was not reached in this trial, and the planned upper limit of hydralazine investigated in this combination was 400 mg/day without grade 3 or 4 toxicities. A median number of two treatment cycles were delivered. One partial response by Response Evaluation Criteria In Solid Tumors criteria was observed, and five subjects experienced stable disease for 3 to 6 months. The combination of hydralazine and valproic acid is simple, nontoxic, and might be appropriate for chemoprevention or combination with other cancer treatments. This trial supports further investigation of epigenetic modification as a new therapeutic strategy.
RESUMO
The ATR-CHEK1 pathway is upregulated and overactivated in Ataxia Telangiectasia (AT) cells, which lack functional ATM protein. Loss of ATM in AT confers radiosensitivity, although ATR-CHEK1 pathway overactivation compensates, leads to prolonged G(2) arrest after treatment with ionizing radiation (IR), and partially reverses the radiosensitivity. We observed similar upregulation of the ATR-CHEK1 pathway in a subset of oral squamous cell carcinoma (OSCC) cell lines with ATM loss. In the present study, we report copy number gain, amplification, or translocation of the ATR gene in 8 of 20 OSCC cell lines by FISH; whereas the CHEK1 gene showed copy number loss in 12 of 20 cell lines by FISH. Quantitative PCR showed overexpression of both ATR and CHEK1 in 7 of 11 representative OSCC cell lines. Inhibition of ATR or CHEK1 with their respective siRNAs resulted in increased sensitivity of OSCC cell lines to IR by the colony survival assay. siRNA-mediated ATR or CHEK1 knockdown led to loss of G(2) cell cycle accumulation and an increased sub-G(0) apoptotic cell population by flow cytometric analysis. In conclusion, the ATR-CHEK1 pathway is upregulated in a subset of OSCC with distal 11q loss and loss of the G(1) phase cell cycle checkpoint. The upregulated ATR-CHEK1 pathway appears to protect OSCC cells from mitotic catastrophe by enhancing the G(2) checkpoint. Knockdown of ATR and/or CHEK1 increases the sensitivity of OSCC cells to IR. These findings suggest that inhibition of the upregulated ATR-CHEK1 pathway may enhance the efficacy of ionizing radiation treatment of OSCC.