AKESOgen Inc.

Norcross, GA, United States

AKESOgen Inc.

Norcross, GA, United States
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Leyland-Jones B.,Avera Cancer Institute | Gray K.P.,Dana-Farber Cancer Institute | Abramovitz M.,VM Institute of Research | Bouzyk M.,AKESOgen Inc. | And 25 more authors.
Breast Cancer Research and Treatment | Year: 2015

Estrogen receptor 1 (ESR1) and ESR2 gene polymorphisms have been associated with endocrine-mediated physiological mechanisms, and inconsistently with breast cancer risk and outcomes, bone mineral density changes, and hot flushes/night sweats. DNA was isolated and genotyped for six ESR1 and two ESR2 single-nucleotide polymorphisms (SNPs) from tumor specimens from 3691 postmenopausal women with hormone receptor-positive breast cancer enrolled in the BIG 1-98 trial to receive tamoxifen and/or letrozole for 5 years. Associations with recurrence and adverse events (AEs) were assessed using Cox proportional hazards models. 3401 samples were successfully genotyped for five SNPs. ESR1 rs9340799(XbaI) (T>C) variants CC or TC were associated with reduced breast cancer risk (HR = 0.82,95 % CI = 0.67–1.0), and ESR1 rs2077647 (T>C) variants CC or TC was associated with reduced distant recurrence risk (HR = 0.69, 95 % CI = 0.53–0.90), both regardless of the treatments. No differential treatment effects (letrozole vs. tamoxifen) were observed for the association of outcome with any of the SNPs. Letrozole-treated patients with rs2077647 (T>C) variants CC and TC had a reduced risk of bone AE (HR = 0.75, 95 % CI = 0.58–0.98, Pinteraction = 0.08), whereas patients with rs4986938 (G>A) genotype variants AA and AG had an increased risk of bone AE (HR = 1.37, 95 % CI = 1.01–1.84, Pinteraction = 0.07). We observed that (1) rare ESR1 homozygous polymorphisms were associated with lower recurrence, and (2) ESR1 and ESR2 SNPs were associated with bone AEs in letrozole-treated patients. Genes that are involved in estrogen signaling and synthesis have the potential to affect both breast cancer recurrence and side effects, suggesting that individual treatment strategies can incorporate not only oncogenic drivers but also SNPs related to estrogen activity. © 2015, Springer Science+Business Media New York.


Regan M.M.,Dana-Farber Cancer Institute | Regan M.M.,Harvard University | Leyland-Jones B.,Emory University | Bouzyk M.,Emory University | And 31 more authors.
Journal of the National Cancer Institute | Year: 2012

Background Adjuvant tamoxifen therapy is effective for postmenopausal women with endocrine-responsive breast cancer. Cytochrome P450 2D6 (CYP2D6) enzyme metabolizes tamoxifen to clinically active metabolites, and CYP2D6 polymorphisms may adversely affect tamoxifen efficacy. In this study, we investigated the clinical relevance of CYP2D6 polymorphisms. MethodsWe obtained tumor tissues and isolated DNA from 4861 of 8010 postmenopausal women with hormone receptor-positive breast cancer who enrolled in the randomized, phase III double-blind Breast International Group (BIG) 1-98 trial between March 1998 and May 2003 and received tamoxifen and/or letrozole treatment. Extracted DNA was used for genotyping nine CYP2D6 single-nucleotide polymorphisms using polymerase chain reaction-based methods. Genotype combinations were used to categorize CYP2D6 metabolism phenotypes as poor, intermediate, and extensive metabolizers (PM, IM, and EM, respectively; n = 4393 patients). Associations of CYP2D6 metabolism phenotypes with breast cancer-free interval (referred to as recurrence) and treatment-induced hot flushes according to randomized endocrine treatment and previous chemotherapy were assessed. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided.Results No association between CYP2D6 metabolism phenotypes and breast cancer-free interval was observed among patients who received tamoxifen monotherapy without previous chemotherapy (P =. 35). PM or IM phenotype had a non-statistically significantly reduced risk of breast cancer recurrence compared with EM phenotype (PM or IM vs EM, HR of recurrence = 0.86, 95% CI = 0.60 to 1.24). CYP2D6 metabolism phenotype was associated with tamoxifen-induced hot flushes (P =. 020). Both PM and IM phenotypes had an increased risk of tamoxifen-induced hot flushes compared with EM phenotype (PM vs EM, HR of hot flushes = 1.24, 95% CI = 0.96 to 1.59; IM vs EM, HR of hot flushes = 1.23, 95% CI = 1.05 to 1.43). Conclusions CYP2D6 phenotypes of reduced enzyme activity were not associated with worse disease control but were associated with increased hot flushes, contrary to the hypothesis. The results of this study do not support using the presence or absence of hot flushes or the pharmacogenetic testing of CYP2D6 to determine whether to treat postmenopausal breast cancer patients with tamoxifen. © 2012 The Author.


PubMed | University of Michigan, AKESOgen Inc., Italian National Cancer Institute, University of Chicago and 11 more.
Type: Clinical Trial, Phase III | Journal: Breast cancer research and treatment | Year: 2015

Estrogen receptor 1 (ESR1) and ESR2 gene polymorphisms have been associated with endocrine-mediated physiological mechanisms, and inconsistently with breast cancer risk and outcomes, bone mineral density changes, and hot flushes/night sweats. DNA was isolated and genotyped for six ESR1 and two ESR2 single-nucleotide polymorphisms (SNPs) from tumor specimens from 3691 postmenopausal women with hormone receptor-positive breast cancer enrolled in the BIG 1-98 trial to receive tamoxifen and/or letrozole for 5 years. Associations with recurrence and adverse events (AEs) were assessed using Cox proportional hazards models. 3401 samples were successfully genotyped for five SNPs. ESR1 rs9340799(XbaI) (T>C) variants CC or TC were associated with reduced breast cancer risk (HR = 0.82,95% CI = 0.67-1.0), and ESR1 rs2077647 (T>C) variants CC or TC was associated with reduced distant recurrence risk (HR = 0.69, 95% CI = 0.53-0.90), both regardless of the treatments. No differential treatment effects (letrozole vs. tamoxifen) were observed for the association of outcome with any of the SNPs. Letrozole-treated patients with rs2077647 (T>C) variants CC and TC had a reduced risk of bone AE (HR = 0.75, 95% CI = 0.58-0.98, P interaction = 0.08), whereas patients with rs4986938 (G>A) genotype variants AA and AG had an increased risk of bone AE (HR = 1.37, 95% CI = 1.01-1.84, P interaction = 0.07). We observed that (1) rare ESR1 homozygous polymorphisms were associated with lower recurrence, and (2) ESR1 and ESR2 SNPs were associated with bone AEs in letrozole-treated patients. Genes that are involved in estrogen signaling and synthesis have the potential to affect both breast cancer recurrence and side effects, suggesting that individual treatment strategies can incorporate not only oncogenic drivers but also SNPs related to estrogen activity.


Dey N.,Sanford Research | Dey N.,University of South Dakota | Barwick B.G.,Winship Cancer Institute | Moreno C.S.,Emory University | And 16 more authors.
BMC Cancer | Year: 2013

Background: Triple Negative subset of (TN) Breast Cancers (BC), a close associate of the basal-like subtype (with limited discordance) is an aggressive form of the disease which convey unpredictable, and poor prognosis due to limited treatment options and lack of proven effective targeted therapies.Methods: We conducted an expression study of 240 formalin-fixed, paraffin-embedded (FFPE) primary biopsies from two cohorts, including 130 TN tumors, to identify molecular mechanisms of TN disease.Results: The annotation of differentially expressed genes in TN tumors contained an overrepresentation of canonical Wnt signaling components in our cohort and others. These observations were supported by upregulation of experimentally induced oncogenic Wnt/β-catenin genes in TN tumors, recapitulated using targets induced by Wnt3A. A functional blockade of Wnt/β-catenin pathway by either a pharmacological Wnt-antagonist, WntC59, sulidac sulfide, or β-catenin (functional read out of Wnt/β-catenin pathway) SiRNA mediated genetic manipulation demonstrated that a functional perturbation of the pathway is causal to the metastasis- associated phenotypes including fibronectin-directed migration, F-actin organization, and invasion in TNBC cells. A classifier, trained on microarray data from β-catenin transfected mammary cells, identified a disproportionate number of TNBC breast tumors as compared to other breast cancer subtypes in a meta-analysis of 11 studies and 1,878 breast cancer patients, including the two cohorts published here. Patients identified by the Wnt/β-catenin classifier had a greater risk of lung and brain, but not bone metastases.Conclusion: These data implicate transcriptional Wnt signaling as a hallmark of TNBC disease associated with specific metastatic pathways. © 2013 Dey et al.; licensee BioMed Central Ltd.


PubMed | Morehouse School of Medicine, Emory University and AKESOgen Inc
Type: | Journal: Gynecologic oncology reports | Year: 2015

Aggressive course and treatment resistance characterize ectopic human chorionic gonadotropin.Recurrence of endometrial cancer with ectopic hCG was treated with brachytherapy and EMACO.The serum hCG level can serve as a marker in tumors with ectopic hCG expression.


Dey N.,Sanford Research | Dey N.,University of South Dakota | Young B.,Sanford Research | Young B.,Scripps Research Institute | And 9 more authors.
PLoS ONE | Year: 2013

Mutations of genes in tumor cells of Triple Negative subset of Breast Cancer (TNBC) deregulate pathways of signal transduction. The loss of tumor suppressor gene PTEN is the most common first event associated with basal-like subtype (Martins, De, Almendro, Gonen, and Park, 2012). Here we report for the first time that the functional upregulation of secreted-MMP7, a transcriptional target of Wnt-β-catenin signature pathway in TNBC is associated to the loss of PTEN. We identified differential expression of mRNAs in several key-components genes, and transcriptional target genes of the Wnt-β-catenin pathway (WP), including beta-catenin, FZD7, DVL1, MMP7, c-MYC, BIRC5, CD44, PPARD, c-MET, and NOTCH1 in FFPE tumors samples from TNBC patients of two independent cohorts. A similar differential upregulation of mRNA/protein for beta-catenin, the functional readout of WP, and for MMP7, a transcriptional target gene of beta-catenin was observed in TNBC cell line models. Genetic or pharmacological attenuation of beta-catenin by SiRNA or WP modulators (XAV939 and sulindac sulfide) and pharmacological mimicking of PTEN following LY294002 treatment downregulated MMP7 levels as well as enzymatic function of the secreted MMP7 in MMP7 positive PTEN-null TNBC cells. Patient data revealed that MMP7 mRNA was high in only a subpopulation of TNBC, and this subpopulation was characterized by a concurrent low expression of PTEN mRNA. In cell lines, a high expression of casein-zymograph-positive MMP7 was distinguished by an absence of functional PTEN. A similar inverse relationship between MMP7 and PTEN mRNA levels was observed in the PAM50 data set (a correlation coefficient of -0.54). The PAM50 subtype and outcome data revealed that the high MMP7 group had low pCR (25%) and High Rd (74%) in clinical stage T3 pathologic response in contrast to the high pCR (40%) and low residual disease (RD) (60%) of the low MMP7 group. © 2013 Dey et al.


Bouzyk M.,AKESOgen Inc.
Pharmacogenomics | Year: 2012

Rapid advancement of genomics, genetic and bioinformatic technologies have paved the way for an explosion of opportunities in pharmacogenomics, which is reflected by the growing number of biomarkers in the 'personalized medicine cabinet'. AKESOgen, Inc. (GA, USA) has been established to meet and champion these needs. AKESOgen, Inc. is a biomarker, genomics and pharmacogenomics contract research organization that services the academic, pharmaceutical, biotechnology and agricultural sectors. AKESOgen, Inc. performs biomarker profiling and genomics services utilizing different types of markers (e.g., DNA, RNA and methylation) for the research and development market. AKESOgen, Inc. establishes and validates biomarkers in the clinical trials arena and provides expertise in biobanking.


Taylor K.C.,University of North Carolina at Chapel Hill | Small C.M.,Emory University | Dominguez C.E.,Hawaii Reproductive Center | Murray L.E.,Emory University | And 4 more authors.
Annals of Epidemiology | Year: 2011

Purpose: Common polymorphisms in the N-acetyltransferase-2 (NAT2) metabolic enzyme determine slow or rapid acetylator phenotypes. We investigated the effects of alcohol, smoking, and caffeine on fecundability, and determined whether the effects were modified by NAT2. Methods: Three NAT2 polymorphisms were genotyped in 319 women office workers participating in a prospective pregnancy study (1990-1994). Women were ages 20-41 and at risk for pregnancy. Discrete-time survival analysis was used to determine the effects of alcohol, smoking, and caffeine on fecundability and evaluate effect modification by NAT2. Results: We followed 319 women (161 slow acetylators, 158 rapid) for an average of 8 menstrual cycles, resulting in 124 pregnancies. There was no effect of caffeine on fecundability. Drinking ≥1 alcoholic drink per day and current smoking were significantly associated with reduced fecundability, but only among slow acetylators (adjusted fecundability odds ratio [FOR] for smoking = 0.34; 95% confidence interval, 0.22-0.90; adjusted FOR for ≥1 drink per day = 0.20; 0.05-0.92). There was no effect among rapid acetylators. Conclusions: NAT2 status significantly modified the effects of alcohol and smoking on fecundability, emphasizing the importance of incorporating genetic and metabolic information in studies of reproductive health. Replication of this study is warranted. © 2011 Elsevier Inc.


Stone B.,Benaroya Research Institute | Rieck M.,Benaroya Research Institute | Rawlings C.A.,Benaroya Research Institute | Kas A.,Benaroya Research Institute | And 3 more authors.
Clinical Immunology | Year: 2012

Therapies capable of generating host T regulatory cells (TR) responsive to donor-specific HLA-class II minor histocompatibility antigens have the potential to promote tolerance of a transplanted organ. Our group has developed a novel approach for the identification of potentially therapeutic TR target antigens. We perform parallel non-synonymous SNP genotyping of HLA-identical subject pairs to identify peptide variations expressed by only one of the two subjects. Variant peptide pairs are then evaluated for binding a shared HLA-class II allele. Minor peptides predicted to bind HLA-class II with greater affinity than the common variant peptide are tested for HLA class II binding and in vitro induction of suppressive CD4+ T cells. Using this approach we have identified multiple pairs of variant peptides capable of differential binding and induction of suppressive CD4+ T cells. These data demonstrate the feasibility of identifying potentially therapeutic HLA class II minor antigens for generation of donor-specific TR. © 2012 Elsevier Inc.


PubMed | AKESOgen Inc.
Type: Journal Article | Journal: Pharmacogenomics | Year: 2012

Rapid advancement of genomics, genetic and bioinformatic technologies have paved the way for an explosion of opportunities in pharmacogenomics, which is reflected by the growing number of biomarkers in the personalized medicine cabinet. AKESOgen, Inc. (GA, USA) has been established to meet and champion these needs. AKESOgen, Inc. is a biomarker, genomics and pharmacogenomics contract research organization that services the academic, pharmaceutical, biotechnology and agricultural sectors. AKESOgen, Inc. performs biomarker profiling and genomics services utilizing different types of markers (e.g., DNA, RNA and methylation) for the research and development market. AKESOgen, Inc. establishes and validates biomarkers in the clinical trials arena and provides expertise in biobanking.

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