Journal of cancer therapeutics & research最新文献

{"title":"The prognostic value of <i>BRCA1</i> promoter methylation in early stage triple negative breast cancer.","authors":"Priyanka Sharma,&nbsp;Shane R Stecklein,&nbsp;Bruce F Kimler,&nbsp;Geetika Sethi,&nbsp;Brian K Petroff,&nbsp;Teresa A Phillips,&nbsp;Ossama W Tawfik,&nbsp;Andrew K Godwin,&nbsp;Roy A Jensen","doi":"10.7243/2049-7962-3-2","DOIUrl":"https://doi.org/10.7243/2049-7962-3-2","url":null,"abstract":"<p><strong>Introduction: </strong>Methylation of the <i>BRCA1</i> promoter is frequent in triple negative breast cancers (TNBC) and results in a tumor phenotype similar to <i>BRCA1</i>-mutated tumors. <i>BRCA1</i> mutation-associated cancers are more sensitive to DNA damaging agents as compared to conventional chemotherapy agents. It is not known if there is an interaction between the presence of <i>BRCA1</i> promoter methylation (PM) and response to chemotherapy agents in sporadic TNBC. We sought to investigate the prognostic significance of <i>BRCA1</i> PM in TNBC patients receiving standard chemotherapy.</p><p><strong>Methods: </strong>Subjects with stage I-III TNBC treated with chemotherapy were identified and their formalin-fixed paraffin-embedded (FFPE) tumor specimens retrieved. Genomic DNA was isolated and subjected to methylation-specific PCR (MSPCR).</p><p><strong>Results: </strong>DNA was isolated from primary tumor of 39 subjects. <i>BRCA1</i> PM was detected in 30% of patients. Presence of <i>BRCA1</i> PM was associated with lower <i>BRCA1</i> transcript levels, suggesting epigenetic <i>BRCA1</i> silencing. All patients received chemotherapy (anthracycline:90%, taxane:69%). At a median follow-up of 64 months, 46% of patients have recurred and 36% have died. On univariate analysis, African-American race, node positivity, stage, and <i>BRCA1</i> PM were associated with worse RFS and OS. Five year OS was 36% for patients with <i>BRCA1</i> PM vs. 77% for patients without <i>BRCA1</i> PM (p=0.004). On multivariable analysis, <i>BRCA1</i> PM was associated with significantly worse RFS and OS.</p><p><strong>Conclusions: </strong>We show that <i>BRCA1</i> PM is common in TNBC and has the potential to identify a significant fraction of TNBC patients who have suboptimal outcomes with standard chemotherapy.</p>","PeriodicalId":90206,"journal":{"name":"Journal of cancer therapeutics & research","volume":"3 2","pages":"1-11"},"PeriodicalIF":0.0,"publicationDate":"2014-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4147783/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32630033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Apoptosis-Related Single Nucleotide Polymorphisms and the Risk of Non-Small Cell Lung Cancer in Women.","authors":"Anand Pathak, Angela S Wenzlaff, Paula L Hyland, Michele L Cote, Greg R Keele, Susan Land, Matthew L Boulton, Ann G Schwartz","doi":"10.7243/2049-7962-3-1","DOIUrl":"10.7243/2049-7962-3-1","url":null,"abstract":"<p><strong>Background: </strong>Germline apoptosis-related single nucleotide polymorphisms (SNPs) have been shown to contribute to the risk of developing non-small cell lung cancer (NSCLC). However, very few studies have looked specifically at apoptosis-related SNPs in a racially-stratified analysis of white and African-American women.</p><p><strong>Methods: </strong>We examined the risk of developing NSCLC associated with 98 germline SNPs in 32 apoptosis-related genes among women in a population-based case-control study from the Detroit metropolitan area. We examined 453 cases of NSCLC and 478 control subjects. We used an unconditional logistic regression with a dominant model, stratified by race, and adjusted for age, pack-years smoked, ever/never smoking status, family history of lung cancer, history of COPD, BMI and education.</p><p><strong>Results: </strong>Our logistic regression identified 3 significant apoptosis-related SNPs in whites (<i>APAF-1,</i> rs1007573; <i>CD40</i> rs3765459, and <i>CD40</i> rs1535045), and 7 significant SNPs (<i>ATM,</i> rs1801516; <i>BAK1,</i> rs513349; <i>TNF,</i> rs1800629; <i>TP63,</i> rs6790167; <i>TP63,</i> rs7613791, <i>TP63,</i> rs35592567 and <i>TP63,</i> rs3856775<i>)</i> in African-Americans. In a downstream analysis, these SNPs were further prioritized utilizing the False Positive Report Percentage (FPRP) methodology and backwards elimination. In whites, <i>APAF-1 (</i>rs1007573), <i>CD40 (</i>rs3765459) and <i>CD40</i> (rs1535045) were all found to be significant by FPRP. In African-Americans, <i>TP63</i> SNPs rs6790167 and rs7613791 were found to have a significant FPRP. In parallel, a backward elimination procedure was used on the 3 significant SNPs in whites and 7 significant SNPs in African-Americans. This procedure identified <i>APAF-1</i> rs1007573 (OR=1.86, 95% CI: 1.17-2.95) and <i>CD40</i> rs1535045 (OR=0.58, 95% CI: 0.40-0.84) as significant independent predictors of risk among whites, and <i>ATM</i> rs1801516 (OR=24.15, 95% CI: 3.50-166.55), <i>TNF</i> rs1800629 (OR= 0.42, 95% CI: 0.18-0.99) and <i>TP63</i> rs6790167 (OR: 2.85, 95% CI: 1.33-6.09) as significant, independent predictors in African-Americans.</p><p><strong>Conclusion: </strong>In whites, only SNPs <i>APAF-1</i> rs1007573 and <i>CD40</i> rs1535045 were significant by both FPRP and backwards elimination, while in African-Americans, only <i>TP63</i> rs6790167 was significant by both methodologies. Thus, we have identified three promising variants associated with increased risk of NSCLC that warrant additional investigation in future studies.</p>","PeriodicalId":90206,"journal":{"name":"Journal of cancer therapeutics & research","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4002173/pdf/nihms-559787.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32309806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PCI-24781 (abexinostat), a novel histone deacetylase inhibitor, induces reactive oxygen species-dependent apoptosis and is synergistic with bortezomib in neuroblastoma.","authors":"Giselle Saulnier Sholler,&nbsp;Erika A Currier,&nbsp;Akshita Dutta,&nbsp;Marni A Slavik,&nbsp;Sharon A Illenye,&nbsp;Maria Cecilia F Mendonca,&nbsp;Julie Dragon,&nbsp;Stephen S Roberts,&nbsp;Jeffrey P Bond","doi":"10.7243/2049-7962-2-21","DOIUrl":"https://doi.org/10.7243/2049-7962-2-21","url":null,"abstract":"<p><p>In this study, we investigated the cytotoxic effects of a broad-spectrum histone deacetylase (HDAC) inhibitor, PCI-24781, alone and in combination with the proteasome inhibitor bortezomib in neuroblastoma cell lines. The combination was shown to induce synergistic cytotoxity involving the formation of reactive oxygen species. The cleavage of caspase-3 and PARP, as determined by western blotting, indicated that cell death was primarily due to apoptosis. Xenograft mouse models indicated increased survival among animals treated with this combination. The Notch signaling pathway and MYCN gene expression were quantified by reverse transcription-polymerase chain reaction (PCR) in cells treated with PCI-24781 and bortezomib, alone and in combination. Notch pathway expression increased in response to an HDAC inhibitor. NFKB1 and MYCN were both significantly down regulated. Our results suggest that PCI-24781 and bortezomib are synergistic in neuroblastoma cell lines and may be a new therapeutic strategy for this disease.</p>","PeriodicalId":90206,"journal":{"name":"Journal of cancer therapeutics & research","volume":"2 ","pages":"21"},"PeriodicalIF":0.0,"publicationDate":"2013-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266584/pdf/nihms640593.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32917318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}