RESUMEN
BACKGROUND: This trial was designed to evaluate the activity and safety of ganetespib in combination with docetaxel in advanced non-small cell lung cancer (NSCLC) and to identify patient populations most likely to benefit from the combination. PATIENTS AND METHODS: Patients with one prior systemic therapy for advanced disease were eligible. Docetaxel (75 mg/m(2) on day 1) was administered alone or with ganetespib (150 mg/m(2) on days 1 and 15) every 3 weeks. The primary end points were progression-free survival (PFS) in two subgroups of the adenocarcinoma population: patients with elevated lactate dehydrogenase (eLDH) and mutated KRAS (mKRAS). RESULTS: Of 385 patients enrolled, 381 were treated. Early in the trial, increased hemoptysis and lack of efficacy were observed in nonadenocarcinoma patients (n = 71); therefore, only patients with adenocarcinoma histology were subsequently enrolled. Neutropenia was the most common grade ≥3 adverse event: 41% in the combination arm versus 42% in docetaxel alone. There was no improvement in PFS for the combination arm in the eLDH (N = 114, adjusted hazard ratio (HR) = 0.77, P = 0.1134) or mKRAS (N = 89, adjusted HR = 1.11, P = 0.3384) subgroups. In the intent-to-treat adenocarcinoma population, there was a trend in favor of the combination, with PFS (N = 253, adjusted HR = 0.82, P = 0.0784) and overall survival (OS) (adjusted HR = 0.84, P = 0.1139). Exploratory analyses showed significant benefit of the ganetespib combination in the prespecified subgroup of adenocarcinoma patients diagnosed with advanced disease >6 months before study entry (N = 177): PFS (adjusted HR = 0.74, P = 0.0417); OS (adjusted HR = 0.69, P = 0.0191). CONCLUSION: Advanced lung adenocarcinoma patients treated with ganetespib in combination with docetaxel had an acceptable safety profile. While the study's primary end points were not met, significant prolongation of PFS and OS was observed in patients >6 months from diagnosis of advanced disease, a subgroup chosen as the target population for the phase III study.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Anciano , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Supervivencia sin Enfermedad , Docetaxel , Femenino , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Humanos , L-Lactato Deshidrogenasa/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Proteínas Proto-Oncogénicas p21(ras)/genética , Taxoides/administración & dosificación , Resultado del Tratamiento , Triazoles/administración & dosificaciónRESUMEN
BACKGROUND: This phase 1 trial utilising a Bayesian continual reassessment method evaluated bortezomib and sunitinib to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and recommended doses of the combination. METHODS: Patients with advanced solid organ malignancies were enrolled and received bortezomib weekly with sunitinib daily for 4 weeks, every 6 weeks. Initial doses were sunitinib 25 mg and bortezomib 1 mg m(-2). Cohort size and dose level estimation was performed utilising the Escalation with Overdose Control (EWOC) adaptive method. Seven dose levels were evaluated; initially, sunitinib was increased to a goal dose of 50 mg with fixed bortezomib, then bortezomib was increased. Efficacy assessment occurred after each cycle using RECIST criteria. RESULTS: Thirty patients were evaluable. During sunitinib escalation, DLTs of grade 4 thrombocytopenia (14%) and neutropenia (6%) at sunitinib 50 mg and bortezomib 1.3 mg m(-2) were seen. Subsequent experience showed tolerability and activity for sunitinib 37.5 mg and bortezomib 1.9 mg m(-2). Common grade 3/4 toxicities were neutropenia, thrombocytopenia, hypertension, and diarrhoea. The recommended doses for further study are bortezomib 1.9 mg m(-2) and sunitinib 37.5 mg. Four partial responses were seen. Stable disease >6 months was noted in an additional six patients. CONCLUSION: Bortezomib and sunitinib are well tolerated and have anticancer activity, particularly in thyroid cancer. A phase 2 study of this combination in thyroid cancer patients is planned.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ácidos Borónicos/administración & dosificación , Indoles/administración & dosificación , Pirazinas/administración & dosificación , Pirroles/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Teorema de Bayes , Bortezomib , Esquema de Medicación , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Sunitinib , Neoplasias de la Tiroides/tratamiento farmacológicoRESUMEN
ONYX-015 is an adenovirus with the E1B 55-kDa gene deleted, engineered to selectively replicate in and lyse p53-deficient cancer cells while sparing normal cells. Although ONYX-015 and chemotherapy have demonstrated anti-tumoral activity in patients with recurrent head and neck cancer, disease recurs rapidly with either therapy alone. We undertook a phase II trial of a combination of intratumoral ONYX-015 injection with cisplatin and 5-fluorouracil in patients with recurrent squamous cell cancer of the head and neck. There were substantial objective responses, including a high proportion of complete responses. By 6 months, none of the responding tumors had progressed, whereas all non-injected tumors treated with chemotherapy alone had progressed. The toxic effects that occurred were acceptable. Tumor biopsies obtained after treatment showed tumor-selective viral replication and necrosis induction.
Asunto(s)
Adenovirus Humanos/genética , Cisplatino/uso terapéutico , Fluorouracilo/uso terapéutico , Terapia Genética/métodos , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/terapia , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/terapia , Adenovirus Humanos/fisiología , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , Terapia Combinada , Femenino , Terapia Genética/efectos adversos , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Replicación ViralRESUMEN
Mitogen-activated protein kinase kinase 3 (MKK3) is a dual threonine/tyrosine protein kinase that regulates inflammation, proliferation and apoptosis through specific phosphorylation and activation of the p38 mitogen-activated protein kinase. However, the role of MKK3 beyond p38-signaling remains elusive. Recently, we reported a protein-protein interaction (PPI) network of cancer-associated genes, termed OncoPPi, as a resource for the scientific community to generate new biological models. Analysis of the OncoPPi connectivity identified MKK3 as one of the major hub proteins in the network. Here, we show that MKK3 interacts with a large number of proteins critical for cell growth and metabolism, including the major oncogenic driver MYC. Multiple complementary approaches were used to demonstrate the direct interaction of MKK3 with MYC in vitro and in vivo. Computational modeling and experimental studies mapped the interaction interface to the MYC helix-loop-helix domain and a novel 15-residue MYC-binding motif in MKK3 (MBM). The MBM in MKK3 is distinct from the known binding sites for p38 or upstream kinases. Functionally, MKK3 stabilized MYC protein, enhanced its transcriptional activity and increased expression of MYC-regulated genes. The defined MBM peptide mimicked the MKK3 effect in promoting MYC activity. Together, the exploration of OncoPPi led to a new biological model in which MKK3 operates by two distinct mechanisms in cellular regulation through its phosphorylation of p38 and its activation of MYC through PPI.
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Proteínas de Unión al ADN/metabolismo , Neoplasias Pulmonares/metabolismo , MAP Quinasa Quinasa 3/metabolismo , Mapas de Interacción de Proteínas , Factores de Transcripción/metabolismo , Línea Celular Tumoral , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/genética , Bases de Datos de Proteínas , Activación Enzimática , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , MAP Quinasa Quinasa 3/genética , Fosforilación , Conformación Proteica , Transducción de Señal/genética , Factores de Transcripción/química , Factores de Transcripción/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Metastases remain the major cause of death from cancer. Recent molecular advances have highlighted the importance of metabolic alterations in cancer cells, including the Warburg effect that describes an increased glycolysis in cancer cells. However, how this altered metabolism contributes to tumour metastasis remains elusive. Here, we report that phosphorylation-induced activation of lactate dehydrogenase A (LDHA), an enzyme that catalyses the interconversion of pyruvate and lactate, promotes cancer cell invasion, anoikis resistance and tumour metastasis. We demonstrate that LDHA is phosphorylated at tyrosine 10 by upstream kinases, HER2 and Src. Targeting HER2 or Src attenuated LDH activity as well as invasive potential in head and neck cancer and breast cancer cells. Inhibition of LDH activity by small hairpin ribonucleic acid or expression of phospho-deficient LDHA Y10F sensitized the cancer cells to anoikis induction and resulted in attenuated cell invasion and elevated reactive oxygen species, whereas such phenotypes were reversed by its product lactate or antioxidant N-acetylcysteine, suggesting that Y10 phosphorylation-mediated LDHA activity promotes cancer cell invasion and anoikis resistance through redox homeostasis. In addition, LDHA knockdown or LDHA Y10F rescue expression in human cancer cells resulted in decreased tumour metastasis in xenograft mice. Furthermore, LDHA phosphorylation at Y10 positively correlated with progression of metastatic breast cancer in clinical patient tumour samples. Our findings demonstrate that LDHA phosphorylation and activation provide pro-invasive, anti-anoikis and pro-metastatic advantages to cancer cells, suggesting that Y10 phosphorylation of LDHA may represent a promising therapeutic target and a prognostic marker for metastatic human cancers.
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Neoplasias de la Mama/enzimología , L-Lactato Deshidrogenasa/metabolismo , Procesamiento Proteico-Postraduccional , Animales , Anoicis/efectos de los fármacos , Antineoplásicos/farmacología , Benzodioxoles/farmacología , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular , Activación Enzimática , Femenino , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , L-Lactato Deshidrogenasa/genética , Lactato Deshidrogenasa 5 , Metástasis Linfática , Ratones Desnudos , Invasividad Neoplásica , Trasplante de Neoplasias , Fosforilación , Quinazolinas/farmacología , Especies Reactivas de Oxígeno , Receptor ErbB-2/metabolismo , Familia-src Quinasas/metabolismoRESUMEN
The oxidative pentose phosphate pathway (PPP) is crucial for cancer cell metabolism and tumor growth. We recently reported that targeting a key oxidative PPP enzyme, 6-phosphogluconate dehydrogenase (6PGD), using our novel small-molecule 6PGD inhibitors Physcion and its derivative S3, shows anticancer effects. Notably, humans with genetic deficiency of either 6PGD or another oxidative PPP enzyme, glucose-6-phosphate dehydrogenase, exhibit non-immune hemolytic anemia upon exposure to aspirin and various antimalarial drugs. Inspired by these clinical observations, we examined the anticancer potential of combined treatment with 6PGD inhibitors and antimalarial drugs. We found that stable knockdown of 6PGD sensitizes leukemia cells to antimalarial agent dihydroartemisinin (DHA). Combined treatment with DHA and Physcion activates AMP-activated protein kinase, leading to synergistic inhibition of human leukemia cell viability. Moreover, our combined therapy synergistically attenuates tumor growth in xenograft nude mice injected with human K562 leukemia cells and cell viability of primary leukemia cells from human patients, but shows minimal toxicity to normal hematopoietic cells in mice as well as red blood cells and mononucleocytes from healthy human donors. Our findings reveal the potential for combined therapy using optimized doses of Physcion and DHA as a novel antileukemia treatment without inducing hemolysis.
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Antimaláricos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Emodina/análogos & derivados , Leucemia/tratamiento farmacológico , Vía de Pentosa Fosfato/efectos de los fármacos , Fosfogluconato Deshidrogenasa/antagonistas & inhibidores , Animales , Antimaláricos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Artemisininas/administración & dosificación , Artemisininas/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Sinergismo Farmacológico , Emodina/administración & dosificación , Emodina/farmacología , Femenino , Humanos , Células K562 , Leucemia/enzimología , Ratones , Ratones Desnudos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Head and neck cancer is a major worldwide health problem; it has been estimated that approximately 900,000 people were diagnosed with this disease in 1995. Patients are generally treated with surgery and/or radiation therapy. Treatment, especially of patients with early stage (I or II) head and neck squamous cell carcinoma, is often successful. A serious concern, however, is the fact that these patients subsequently develop second primary tumors at an annual rate of 4%-7%. Molecular analyses of premalignant and malignant tissues have produced strong evidence that clonal genetic alterations occur during the early stage of aerodigestive tract carcinogenesis. Although the roles of tobacco and diet in head and neck carcinogenesis have been the subjects of epidemiologic investigations for many years, it has only recently become possible to integrate information regarding genetic susceptibility factors into the development of comprehensive risk models for these cancers. The molecular and epidemiologic studies provide the foundation on which clinical trials can be designed to evaluate the role of retinoids and other compounds in the reversal of premalignancy and the prevention of second primary tumors (i.e., in chemoprevention). This translational approach has led to studies of the utility of intermediate end point markers, such as the nuclear retinoic acid receptors, in chemoprevention strategies. Given the rapid advances occurring in this area of research, it may soon be possible to use these biomarkers to identify patients who are most at risk for developing head and neck cancer and who are most likely to benefit from chemopreventive interventions.
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Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/etiología , Neoplasias de Cabeza y Cuello/prevención & control , Retinoides/farmacología , Biomarcadores de Tumor/sangre , Dieta/efectos adversos , Predisposición Genética a la Enfermedad , Genotipo , Neoplasias de Cabeza y Cuello/sangre , Neoplasias de Cabeza y Cuello/epidemiología , Neoplasias de Cabeza y Cuello/genética , Humanos , Incidencia , Neoplasias Primarias Secundarias/tratamiento farmacológico , Neoplasias Primarias Secundarias/prevención & control , Valor Predictivo de las Pruebas , Ensayos Clínicos Controlados Aleatorios como Asunto , Retinoides/farmacocinética , Retinoides/uso terapéutico , Riesgo , Fumar/efectos adversos , Vitamina A/uso terapéutico , beta Caroteno/uso terapéuticoRESUMEN
BACKGROUND: Death-associated protein (DAP) kinase is a serine/threonine kinase that is important in ligand-induced programmed cell death and plays an important role in lung cancer metastasis in animal models. Hypermethylation of the promoter represses the expression of the DAP kinase gene. Our purpose was to determine whether the hypermethylation status of the DAP kinase promoter influences the prognosis of non-small-cell lung cancer (NSCLC). METHODS: We retrospectively studied 135 patients with pathologic stage I NSCLC who had undergone curative surgery. Methylation-specific polymerase chain reaction was used to determine the methylation status of the DAP kinase promoter in resected specimens from patients with primary NSCLC. Statistical analyses, all two-sided, were performed to determine the prognostic effect of methylation status on various clinical parameters. RESULTS: Hypermethylation of the DAP kinase promoter was found in 59 (44%) of the 135 tumors. Patients whose tumors exhibited such hypermethylation had a statistically significantly poorer probability of overall survival at 5 years after surgery than those without such hypermethylation (.46 versus.68; P: =.007). Moreover, the groups with and without hypermethylation of the DAP kinase promoter showed a striking difference in the probability of disease-specific survival; i.e., among people who died of lung cancer-related causes specifically, the probability of 5-year survival was.56 for those with such hypermethylation and.92 for those without it (P:<.001). Multivariate analysis indicated that hypermethylation of the DAP kinase promoter is the only independent predictor for disease-specific survival among clinical and histologic parameters tested. CONCLUSIONS: Hypermethylation of the DAP kinase promoter is a common abnormality in early-stage NSCLC. This abnormality is strongly associated with survival, suggesting that DAP kinase plays an important role in determining the biologic aggressiveness of early-stage NSCLC.
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Proteínas Quinasas Dependientes de Calcio-Calmodulina/genética , Carcinoma de Pulmón de Células no Pequeñas/enzimología , ADN de Neoplasias/metabolismo , Neoplasias Pulmonares/enzimología , Regiones Promotoras Genéticas , Adenocarcinoma/enzimología , Anciano , Proteínas Reguladoras de la Apoptosis , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Carcinoma de Células Escamosas/enzimología , Proteínas Quinasas Asociadas a Muerte Celular , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Masculino , Metilación , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Reacción en Cadena de la Polimerasa , Valor Predictivo de las Pruebas , Pronóstico , Estudios RetrospectivosRESUMEN
BACKGROUND: Lung cancer risk remains elevated for many years after quitting smoking. To assess using proliferation indices in bronchial tissues as an intermediate endpoint biomarker in lung cancer chemoprevention trials, we determined the relationship between the extent, intensity, and cessation of tobacco smoking and proliferative changes in bronchial epithelial biopsy specimens. METHODS: Bronchial biopsy specimens were obtained from up to six epithelial sites in 120 current smokers (median pack-years, 42) and 207 former smokers (median pack-years, 40; median quit-years, 8.1). Sections from the paraffin-embedded specimens were stained with hematoxylin--eosin to determine the metaplasia index and with an antibody to Ki-67 to determine the proliferative (labeling) index for the basal and parabasal (Ki-67 PLI) layers. All statistical tests were two-sided. RESULTS: Biopsy sites with metaplasia had statistically significantly higher Ki-67-labeling indices than those without metaplasia (P<.001) in both current and former smokers. Increased proliferation was observed in multiple biopsy sites, with the average Ki-67 PLI of the subject strongly correlating with the metaplasia index (r =.72 for current smokers; P<.001), even in sites without metaplasia (r =.23 for current smokers; P<.001). In current smokers, the Ki-67 PLI was associated with the number of packs smoked/day (P =.02) but not with smoking years or pack-years. In subjects who had quit smoking, the Ki-67 PLI dropped statistically significantly within 1 year (P =.008) but remained detectable for more than 20 years, even in the absence of squamous metaplasia. CONCLUSION: Smoking appears to elicit a dose-related proliferative response in the bronchial epithelia of active smokers. Although the proliferative response decreased gradually in former smokers, a subset of individuals had detectable proliferation for many years and may benefit from targeted chemoprevention. Bronchial epithelial proliferation, measured by Ki-67, may provide a useful biomarker in the assessment of lung cancer risk and in the response to chemopreventive interventions.
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Biomarcadores de Tumor/análisis , Células Epiteliales/patología , Pulmón/patología , Cese del Hábito de Fumar , Fumar/efectos adversos , Adulto , Anciano , Biopsia , División Celular , Células Epiteliales/inmunología , Femenino , Humanos , Inmunohistoquímica , Antígeno Ki-67/análisis , Pulmón/inmunología , Masculino , Metaplasia , Persona de Mediana Edad , Factores de TiempoRESUMEN
BACKGROUND: New methods are needed to detect precancerous lesions in lung tissue. We conducted a study to determine the utility of LIFE (laser-induced fluorescence emission) autofluorescence bronchoscopy for the detection of squamous metaplasia and dysplasia in current and former smokers. METHODS: In this prospective, single-center study, 53 participants underwent standard white-light bronchoscopy and 39 underwent both white-light and LIFE bronchoscopy. Bronchial biopsy specimens were obtained from all participants at six pre-determined sites using white-light bronchoscopy and from all other sites that appeared to be abnormal in participants who underwent LIFE bronchoscopy. Relationships between LIFE imaging and histologic findings were examined for 245 biopsy specimens obtained from those participants who had undergone LIFE bronchoscopy. RESULTS: LIFE imaging revealed abnormalities designated as either class II or class III in 89 (36.3%) and 16 (6.5%) of the 245 sites examined, respectively, and histopathologic examination showed dysplasia and metaplasia in eight (3.3%) and in 52 (21.2%) of the 245 specimens, respectively. Among the 105 biopsy specimens obtained from sites with abnormal LIFE imaging, only 26 (24.8%) exhibited squamous metaplasia and/or dysplasia, similar to the findings for sites with normal LIFE imaging (34 [24.3%] of 140). Comparison of individuals examined by LIFE imaging with those who underwent white-light bronchoscopy alone revealed no increase in the detection of dysplasia or metaplasia with LIFE bronchoscopy. CONCLUSION: In this population of current and former smokers, abnormalities detected by LIFE bronchoscopy did not improve the detection of squamous metaplasia or dysplasia.
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Broncoscopía , Carcinoma de Células Escamosas/diagnóstico , Fluorescencia , Rayos Láser , Neoplasias Pulmonares/diagnóstico , Fumar/efectos adversos , Adulto , Anciano , Broncoscopía/métodos , Carcinoma de Células Escamosas/etiología , Diagnóstico Diferencial , Femenino , Humanos , Neoplasias Pulmonares/etiología , Masculino , Metaplasia/diagnóstico , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
BACKGROUND AND PURPOSE: Genetic damage has been identified at multiple chromosomal sites (i.e., loci) in lung cancer cells. We questioned whether similar damage could be detected in the bronchial epithelial cells of chronic smokers who do not have this disease. METHODS: Biopsy specimens from six different bronchial regions were obtained from 54 chronic smokers (40 current smokers and 14 former smokers). The presence of squamous metaplasia and dysplasia (abnormal histologic changes) in the specimens was documented by examination of hematoxylin-eosin-stained sections, and a metaplasia index ([number of biopsy specimens with metaplasia/total number of biopsy specimens] x 100%) was calculated for each subject. Loss of heterozygosity (i.e., loss of DNA sequences from one member of a chromosome pair) involving microsatellite DNA at three specific loci-chromosome 3p14, chromosome 9p21, and chromosome 17p13-was evaluated by means of the polymerase chain reaction. Fisher's exact test and logistic regression analysis were used to assess the data. Reported P values are two-sided. RESULTS: Data on microsatellite DNA status at chromosomes 3p14, 9p21, and 17p13 were available for 54, 50, and 44 subjects, respectively. The numbers of individuals who were actually informative (i.e., able to be evaluated for a loss of heterozygosity) at the three loci were 36 (67%), 37 (74%), and 34 (77%), respectively. DNA losses were detected in 27 (75%), 21 (57%), and six (18%) of the informative subjects at chromosomes 3p14, 9p21, and 17p13, respectively. Fifty-one subjects were informative for at least one of the three loci, and 39 (76%) exhibited a loss of heterozygosity. Forty-two subjects were informative for at least two of the loci, and 13 (31%) exhibited losses at a minimum of two loci. Loss of heterozygosity at chromosome 3p14 was more frequent in current smokers (22 [88%] of 25 informative) than in former smokers (five [45%] of 11 informative) (P = .01) and in subjects with a metaplasia index greater than or equal to 15% (21 [91%] of 23 informative) than in subjects with a metaplasia index of less than 15% (six [46%] of 13 informative) (P = .003). In five informative individuals among nine tested nonsmokers, a loss of heterozygosity was detected in only one subject at chromosome 3p14 (P = .03), and no losses were detected at chromosome 9p21 (P = .05). CONCLUSIONS: Genetic alterations at chromosomal sites containing putative tumor-suppressor genes (i.e., 3p14 and the FHIT gene, 9p21 and the p16 gene [also known as CDKN2], and 17p13 and the p53 gene [also known as TP53]) occur frequently in the histologically normal or minimally altered bronchial epithelium of chronic smokers.
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Deleción Cromosómica , Cromosomas Humanos Par 17 , Cromosomas Humanos Par 3 , Cromosomas Humanos Par 9 , Daño del ADN , Neoplasias Pulmonares/genética , Fumar/efectos adversos , Adulto , Anciano , Análisis de Varianza , ADN de Neoplasias/genética , Femenino , Heterocigoto , Humanos , Neoplasias Pulmonares/etiología , Masculino , Repeticiones de Microsatélite , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Estudios ProspectivosRESUMEN
BACKGROUND: Promising data have suggested that retinoid chemoprevention may help to control second primary tumors (SPTs), recurrence, and mortality of stage I non-small-cell lung cancer (NSCLC) patients. METHODS: We carried out a National Cancer Institute (NCI) Intergroup phase III trial (NCI #I91-0001) with 1166 patients with pathologic stage I NSCLC (6 weeks to 3 years from definitive resection and no prior radiotherapy or chemotherapy). Patients were randomly assigned to receive a placebo or the retinoid isotretinoin (30 mg/day) for 3 years in a double-blind fashion. Patients were stratified at randomization by tumor stage, histology, and smoking status. The primary endpoint (time to SPT) and the secondary endpoints (times to recurrence and death) were analyzed by log-rank test and the Cox proportional hazards model. All statistical tests were two-sided. RESULTS: After a median follow-up of 3.5 years, there were no statistically significant differences between the placebo and isotretinoin arms with respect to the time to SPTs, recurrences, or mortality. The unadjusted hazard ratio (HR) of isotretinoin versus placebo was 1.08 (95% confidence interval [CI] = 0.78 to 1.49) for SPTs, 0.99 (95% CI = 0.76 to 1.29) for recurrence, and 1.07 (95% CI = 0.84 to 1.35) for mortality. Multivariate analyses showed that the rate of SPTs was not affected by any stratification factor. Rate of recurrence was affected by tumor stage (HR for T(2) versus T(1) = 1.77 [95% CI = 1.35 to 2.31]) and a treatment-by-smoking interaction (HR for treatment-by-current-versus-never-smoking status = 3.11 [95% CI = 1.00 to 9.71]). Mortality was affected by tumor stage (HR for T(2) versus T(1) = 1.39 [95% CI = 1.10 to 1.77]), histology (HR for squamous versus nonsquamous = 1.31 [95% CI = 1.03 to 1.68]), and a treatment-by-smoking interaction (HR for treatment-by-current-versus-never-smoking = 4.39 [95% CI = 1.11 to 17.29]). Mucocutaneous toxicity (P<.001) and noncompliance (40% versus 25% at 3 years) were higher in the isotretinoin arm than in the placebo arm. CONCLUSIONS: Isotretinoin treatment did not improve the overall rates of SPTs, recurrences, or mortality in stage I NSCLC. Secondary multivariate and subset analyses suggested that isotretinoin was harmful in current smokers and beneficial in never smokers.
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Anticarcinógenos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/prevención & control , Isotretinoína/uso terapéutico , Neoplasias Pulmonares/prevención & control , Neoplasias Primarias Secundarias/prevención & control , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Neoplasias Primarias Secundarias/patología , Placebos , Fumar/efectos adversosRESUMEN
BACKGROUND: Preclinical studies in animal models have demonstrated tumor regression following intratumoral administration of an adenovirus vector containing wild-type p53 complementary DNA (Ad-p53). Therefore, in a phase I clinical trial, we administered Ad-p53 to 28 patients with non-small-cell lung cancer (NSCLC) whose cancers had progressed on conventional treatments. METHODS: Patients received up to six, monthly intratumoral injections of Ad-p53 by use of computed tomography-guided percutaneous fine-needle injection (23 patients) or bronchoscopy (five patients). The doses ranged from 10(6) plaque-forming units (PFU) to 10(11) PFU. RESULTS: Polymerase chain reaction (PCR) analysis showed the presence of adenovirus vector DNA in 18 (86%) of 21 patients with evaluable posttreatment biopsy specimens; vector-specific p53 messenger RNA was detected by means of reverse transcription-PCR analysis in 12 (46%) of 26 patients. Apoptosis (programmed cell death) was demonstrated by increased terminal deoxynucleotide transferase-mediated biotin uridine triphosphate nick-end labeling (TUNEL) staining in posttreatment biopsy specimens from 11 patients. Vector-related toxicity was minimal (National Cancer Institute's Common Toxicity Criteria: grade 3 = one patient; grade 4 = no patients) in 84 courses of treatment, despite repeated injections (up to six) in 23 patients. Therapeutic activity in 25 evaluable patients included partial responses in two patients (8%) and disease stabilization (range, 2-14 months) in 16 patients (64%); the remaining seven patients (28%) exhibited disease progression. CONCLUSIONS: Repeated intratumoral injections of Ad-p53 appear to be well tolerated, result in transgene expression of wild-type p53, and seem to mediate antitumor activity in a subset of patients with advanced NSCLC.
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Adenoviridae , Carcinoma de Pulmón de Células no Pequeñas/terapia , Técnicas de Transferencia de Gen , Genes p53 , Terapia Genética/métodos , Neoplasias Pulmonares/terapia , Adenoviridae/genética , Adulto , Anciano , Broncoscopía , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , ADN Viral/aislamiento & purificación , Progresión de la Enfermedad , Femenino , Genes p53/genética , Vectores Genéticos/efectos adversos , Humanos , Etiquetado Corte-Fin in Situ , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Selección de Paciente , Análisis de Supervivencia , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
ONYX-015 is an E1B-55kDa gene-deleted adenovirus engineered to selectively replicate in and lyse p53-deficient cancer cells. To evaluate the selectivity of ONYX-015 replication and cytopathic effects for the first time in humans, we carried out a Phase II clinical testing of intratumoral and peritumoral ONYX-015 injection in 37 patients with recurrent head and neck carcinoma. Patients received ONYX-015 at a daily dose of 1 x 10(10) plaque-forming units (pfu) via intratumoral injection for 5 days during week 1 of each 3-week cycle (n = 30; cohort A), or 1 x 10(10) pfu twice a day for 10 days during weeks 1 and 2 of each 3-week cycle. Posttreatment biopsies documented selective ONYX-015 presence and/or replication in the tumor tissue of 7 of 11 patients biopsied on days 5-14, but not in immediately adjacent normal tissue (0 of 11 patients; P = 0.01). Tissue destruction was also highly selective; significant tumor regression (>50%) occurred in 21% of evaluable patients, whereas no toxicity to injected normal peritumoral tissues was demonstrated. p53 mutant tumors were significantly more likely to undergo ONYX-015-induced necrosis (7 of 12) than were p53 wild-type tumors (0 of 7; P = 0.017). High neutralizing antibody titers did not prevent infection and/or replication within tumors. ONYX-015 is the first genetically engineered replication-competent virus to demonstrate selective intratumoral replication and necrosis in patients. This agent demonstrates the promise of replication-selective viruses as a novel therapeutic platform against cancer.
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Adenovirus Humanos/fisiología , Carcinoma de Células Escamosas/terapia , Genes p53/genética , Neoplasias de Cabeza y Cuello/terapia , Recurrencia Local de Neoplasia/terapia , Proteínas E1B de Adenovirus/genética , Adenovirus Humanos/genética , Anciano , Anticuerpos Antineoplásicos/biosíntesis , Anticuerpos Antineoplásicos/sangre , Biopsia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/virología , Femenino , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/virología , Humanos , Inyecciones Intralesiones , Masculino , Persona de Mediana Edad , Mutación , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/virología , Replicación ViralRESUMEN
Abnormalities of FHIT, a candidate tumor suppressor gene at 3p14.2, have been found frequently in multiple tumor types including non-small cell lung cancer (NSCLC). To investigate whether FHIT inactivation plays a role in early lung tumorigenesis, Fhit levels were determined by immunohistochemistry in tumors from 87 patients with stage I NSCLC and in 372 bronchial biopsy specimens from 86 chronic smokers without evidence of malignancy. We found that 49% of NSCLC specimens demonstrated significantly decreased staining or lack of staining for Fhit. However, Fhit expression status was not significantly associated with disease-free survival or overall survival. Analysis of a subset of 76 specimens on which microsatellite analysis at the FHIT locus was performed did not show a strong association between loss of heterozygosity at FHIT and Fhit expression, suggesting the presence of complex mechanisms of Fhit inactivation. Of 372 bronchial biopsies from chronic smokers, 86 biopsies (23%) exhibited decreased Fhit expression or lack of Fhit expression. In 37 of 86 (43%) subjects, decreased Fhit expression or lack of expression was observed in at least one biopsy site. Loss of Fhit expression was significantly higher in bronchial metaplastic lesions (23 of 49 lesions, 47%) than in histologically normal bronchial epithelium (63 of 323 specimens, 20%; P < 0.001). Smokers with a metaplasia index of > 15% had a higher frequency of loss of Fhit expression than those with a metaplasia index of < or = 15% (P = 0.015). Interestingly, current smokers had a higher rate of loss of Fhit expression than former smokers (P = 0.02). Our data indicate that Fhit expression is significantly reduced in a substantial number of early-stage NSCLC and preneoplastic lesions in chronic smokers. The association between cigarette smoking and Fhit expression suggests a role for FHIT in the initiation of smoking-related lung tumorigenesis.
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Ácido Anhídrido Hidrolasas , Carcinoma de Pulmón de Células no Pequeñas/genética , Cromosomas Humanos Par 3 , Pérdida de Heterocigocidad , Neoplasias Pulmonares/genética , Pulmón/metabolismo , Proteínas/genética , Fumar/genética , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Mapeo Cromosómico , Femenino , Genes Supresores de Tumor , Humanos , Pulmón/patología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Estadificación de Neoplasias , Fumar/patología , Tasa de SupervivenciaRESUMEN
Cyclin B1 is a key molecule for G2-M-phase transition during the cell cycle and is overexpressed in various tumor types. However, the expression status of cyclin B1 in lung cancer and its clinical significance remain unknown. We used immunohistochemistry studies to examine the expression of cyclin B1 in 77 non-small cell lung cancer specimens from patients with histological stage I disease. All of the patients underwent curative surgical treatment. The median length of follow-up care is 8.2 years. High-level cyclin B1 expression (a cyclin B1 labeling index > or =15%) was observed in 17 of the 77 (22%) tumors. Patients whose tumors expressed a high level of cyclin B1 had a significantly shorter survival time than patients whose tumors expressed a low level of cyclin B1 (P = 0.02, log-rank test). Interestingly, overexpression of cyclin B1 was more frequently observed in tumors with squamous cell histology than in tumors with other histological cell types (P = 0.01, Fisher's exact test). A subgroup analysis revealed that cyclin B1 overexpression seems to be an adverse prognostic factor only in patients with squamous cell carcinoma (SCC) of the lung (P = 0.02, log-rank test). Our data indicate that cyclin B1 may be dysregulated in non-small cell lung cancer, particularly in the SCC subtype, and that a high level of cyclin B1 expression may be a prognostic marker for patients with early-stage SCC of the lung.
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Biomarcadores de Tumor/biosíntesis , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Ciclina B/biosíntesis , Neoplasias Pulmonares/metabolismo , Anciano , Carcinoma de Pulmón de Células no Pequeñas/patología , Ciclina B1 , Femenino , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Análisis de SupervivenciaRESUMEN
Cancer cells feature increased de novo lipogenesis. Sterol regulatory element-binding protein 1 (SREBP1), when presented in its mature form (mSREBP1), enhances lipogenesis by increasing transcription of several of its target genes. Mammalian target of rapamycin (mTOR) complexes, mTORC1 and mTORC2, are master regulators of cellular survival, growth and metabolism. A role for mTORC1 in the regulation of SREBP1 activity has been suggested; however, the connection between mTORC2 and SREBP1 has not been clearly established and hence is the focus of this study. mTOR kinase inhibitors (for example, INK128), which inhibit both mTORC1 and mTORC2, decreased mSREBP1 levels in various cancer cell lines. Knockdown of rictor, but not raptor, also decreased mSREBP1. Consistently, reduced mSREBP1 levels were detected in cells deficient in rictor or Sin1 compared with parent or rictor-deficient cells with re-expression of ectopic rictor. Hence it is mTORC2 inhibition that causes mSREBP1 reduction. As a result, expression of the mSREBP1 target genes acetyl-CoA carboxylase and fatty-acid synthase was suppressed, along with suppressed lipogenesis in cells exposed to INK128. Moreover, mSREBP1 stability was reduced in cells treated with INK128 or rictor knockdown. Inhibition of proteasome, GSK3 or the E3 ubiquitin ligase, FBXW7, prevented mSREBP1 reduction induced by mTORC2 inhibition. Thus mTORC2 inhibition clearly facilitates GSK3-dependent, FBXW7-mediated mSREBP1 degradation, leading to mSREBP1 reduction. Accordingly, we conclude that mTORC2 positively regulates mSREBP1 stability and lipogenesis. Our findings reveal a novel biological function of mTORC2 in the regulation of lipogenesis and warrant further study in this direction.
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Proteínas de Ciclo Celular/metabolismo , Proteínas F-Box/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Complejos Multiproteicos/antagonistas & inhibidores , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Inhibidores Enzimáticos/farmacología , Proteínas F-Box/genética , Proteína 7 que Contiene Repeticiones F-Box-WD , Técnicas de Silenciamiento del Gen , Células HCT116 , Humanos , Indoles/farmacología , Lipogénesis , Maleimidas/farmacología , Diana Mecanicista del Complejo 2 de la Rapamicina , Complejos Multiproteicos/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Serina-Treonina Quinasas TOR/metabolismo , Transfección , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Inhibition of B-Raf/MEK/ERK signaling is an effective therapeutic strategy against certain types of cancers such as melanoma and thyroid cancer. While demonstrated to be effective anticancer agents, B-Raf or MEK inhibitors have also been associated with early tumor progression and development of secondary neoplasms. The ligation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with its receptor, death receptor 5 (DR5), leading to induction of apoptosis, offers a promising anticancer strategy. Importantly, this is also a natural immunosurveillance mechanism against cancer development. We previously demonstrated that activated B-Raf/MEK/ERK signaling positively regulates DR5 expression. Hence, our current work sought to address whether B-Raf/MEK/ERK inhibition and the consequent suppression of DR5 expression impede cancer cell response to DR5 activation-induced apoptosis and activated immune cell-induced killing. We found that both B-Raf (for example, PLX4032) and MEK inhibitors (for example, AZD6244 and PD0325901) effectively inhibited ERK1/2 phosphorylation and reduced DR5 levels in both human thyroid cancer and melanoma cells. Similar to the observed effect of genetic knockdown of the B-Raf gene, pre-treatment of cancer cell lines with either B-Raf or MEK inhibitors attenuated or abolished cellular apoptotic response induced by TRAIL or the DR5 agonistic antibody AMG655 or cell killing by activated T cells. Our findings clearly show that inhibition of B-Raf/MEK/ERK signaling suppresses DR5 expression and impairs DR5 activation-induced apoptosis and T cell-mediated killing of cancer cells. These findings suggest a potential negative impact of B-Raf or MEK inhibition on TRAIL- or DR5-mediated anticancer therapy and on TRAIL/DR5-mediated immune-clearance of cancer cells.
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Inhibidores Enzimáticos/farmacología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Quinasas Quinasa Quinasa PAM/metabolismo , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Apoptosis/efectos de los fármacos , Bencimidazoles/farmacología , Línea Celular Tumoral/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Humanos , Indoles/farmacología , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , ARN Interferente Pequeño , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/genética , Transducción de Señal/efectos de los fármacos , Sulfonamidas/farmacología , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , VemurafenibRESUMEN
Metastasis is responsible for >90% of cancer-related deaths. Complex signaling in cancer cells orchestrates the progression from a primary to a metastatic cancer. However, the mechanisms of these cellular changes remain elusive. We previously demonstrated that p90 ribosomal S6 kinase 2 (RSK2) promotes tumor metastasis. Here we investigated the role of RSK2 in the regulation of microtubule dynamics and its potential implication in cancer cell invasion and tumor metastasis. Stable knockdown of RSK2 disrupted microtubule stability and decreased phosphorylation of stathmin, a microtubule-destabilizing protein, at serine 16 in metastatic human cancer cells. We found that RSK2 directly binds and phosphorylates stathmin at the leading edge of cancer cells. Phosphorylation of stathmin by RSK2 reduced stathmin-mediated microtubule depolymerization. Moreover, overexpression of phospho-mimetic mutant stathmin S16D significantly rescued the decreased invasive and metastatic potential mediated by RSK2 knockdown in vitro and in vivo. Furthermore, stathmin phosphorylation positively correlated with RSK2 expression and metastatic cancer progression in primary patient tumor samples. Our finding demonstrates that RSK2 directly phosphorylates stathmin and regulates microtubule polymerization to provide a pro-invasive and pro-metastatic advantage to cancer cells. Therefore, the RSK2-stathmin pathway represents a promising therapeutic target and a prognostic marker for metastatic human cancers.
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Neoplasias Pulmonares/genética , Metástasis de la Neoplasia/genética , Proteínas Quinasas S6 Ribosómicas 90-kDa/genética , Estatmina/genética , Células A549 , Movimiento Celular/genética , Técnicas de Silenciamiento del Gen , Humanos , Neoplasias Pulmonares/patología , Microtúbulos/genética , Microtúbulos/patología , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Metástasis de la Neoplasia/patología , Fosforilación , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Transducción de Señal , Estatmina/metabolismoRESUMEN
PURPOSE: This trial was designed to determine the maximum-tolerated dose, toxicity, and pharmacology of oral green tea extract (GTE) once daily or three times daily. PATIENTS AND METHODS: Cohorts of three or more adult cancer patients were administered oral GTE with water after meals one or three times daily for 4 weeks, to a maximum of 6 months, depending on disease response and patient tolerance. Pharmacokinetic analyses were encouraged but optional. RESULTS: Dose levels of 0.5 to 5.05 g/m(2) qd and 1.0 to 2.2 g/m(2) tid were explored. A total of 49 patients were studied. PATIENT CHARACTERISTICS: median age, 57 years (range, 27 to 77 years); 23 patients were women (47%); 98% had a Zubrod PS of 1%; 98% had PS of 1; and 21 had non-small-cell lung, 19 had head & neck cancer, three had mesothelioma, and six had other. Mild to moderate toxicities were seen at most dose levels and promptly reversed on discontinuation of GTE. Dose-limiting toxicities were caffeine related and included neurologic and gastrointestinal effects. The maximum-tolerated dose was 4.2 g/m(2) once daily or 1.0 g/m(2) three times daily. No major responses occurred; 10 patients with stable disease completed 6 months of GTE. Pharmacokinetic analyses found accumulation of caffeine levels that were dose dependent, whereas epigallocatechin gallate levels did not accumulate nor appear dose related. CONCLUSION: A dose of 1.0 g/m(2) tid (equivalent to 7 to 8 Japanese cups [120 mL] of green tea three times daily) is recommended for future studies. The side effects of this preparation of GTE were caffeine related. Oral GTE at the doses studied can be taken safely for at least 6 months.