@article{gonzalez_small_green_akhtari_havener_quintanilha_cipriani_reif_mcleod_motsinger-reif_et al._2023, title={RYK Gene Expression Associated with Drug Response Variation of Temozolomide and Clinical Outcomes in Glioma Patients}, volume={16}, ISSN={["1424-8247"]}, url={https://doi.org/10.3390/ph16050726}, DOI={10.3390/ph16050726}, abstractNote={Temozolomide (TMZ) chemotherapy is an important tool in the treatment of glioma brain tumors. However, variable patient response and chemo-resistance remain exceptionally challenging. Our previous genome-wide association study (GWAS) identified a suggestively significant association of SNP rs4470517 in the RYK (receptor-like kinase) gene with TMZ drug response. Functional validation of RYK using lymphocytes and glioma cell lines resulted in gene expression analysis indicating differences in expression status between genotypes of the cell lines and TMZ dose response. We conducted univariate and multivariate Cox regression analyses using publicly available TCGA and GEO datasets to investigate the impact of RYK gene expression status on glioma patient overall (OS) and progression-free survival (PFS). Our results indicated that in IDH mutant gliomas, RYK expression and tumor grade were significant predictors of survival. In IDH wildtype glioblastomas (GBM), MGMT status was the only significant predictor. Despite this result, we revealed a potential benefit of RYK expression in IDH wildtype GBM patients. We found that a combination of RYK expression and MGMT status could serve as an additional biomarker for improved survival. Overall, our findings suggest that RYK expression may serve as an important prognostic or predictor of TMZ response and survival for glioma patients.}, number={5}, journal={PHARMACEUTICALS}, author={Gonzalez, Ricardo D. and Small, George W. and Green, Adrian J. and Akhtari, Farida S. and Havener, Tammy M. and Quintanilha, Julia C. F. and Cipriani, Amber B. and Reif, David M. and McLeod, Howard L. and Motsinger-Reif, Alison A. and et al.}, year={2023}, month={May} }
 @article{green_anchang_akhtari_reif_motsinger-reif_2021, title={Extending the lymphoblastoid cell line model for drug combination pharmacogenomics}, volume={22}, ISSN={["1744-8042"]}, url={https://doi.org/10.2217/pgs-2020-0160}, DOI={10.2217/pgs-2020-0160}, abstractNote={ Combination drug therapies have become an integral part of precision oncology, and while evidence of clinical effectiveness continues to grow, the underlying mechanisms supporting synergy are poorly understood. Immortalized human lymphoblastoid cell lines (LCLs) have been proven as a particularly useful, scalable and low-cost model in pharmacogenetics research, and are suitable for elucidating the molecular mechanisms of synergistic combination therapies. In this review, we cover the advantages of LCLs in synergy pharmacogenomics and consider recent studies providing initial evidence of the utility of LCLs in synergy research. We also discuss several opportunities for LCL-based systems to address gaps in the research through the expansion of testing regimens, assessment of new drug classes and higher-order combinations, and utilization of integrated omics technologies. }, number={9}, journal={PHARMACOGENOMICS}, publisher={Future Medicine Ltd}, author={Green, Adrian J. and Anchang, Benedict and Akhtari, Farida S. and Reif, David M. and Motsinger-Reif, Alison}, year={2021}, month={May} }
 @article{akhtari_green_small_havener_house_roell_reif_mcleod_wiltshire_motsinger-reif_2021, title={High-throughput screening and genome-wide analyses of 44 anticancer drugs in the 1000 Genomes cell lines reveals an association of the NQO1 gene with the response of multiple anticancer drugs}, volume={17}, ISSN={["1553-7404"]}, url={https://doi.org/10.1371/journal.pgen.1009732}, DOI={10.1371/journal.pgen.1009732}, abstractNote={Cancer patients exhibit a broad range of inter-individual variability in response and toxicity to widely used anticancer drugs, and genetic variation is a major contributor to this variability. To identify new genes that influence the response of 44 FDA-approved anticancer drug treatments widely used to treat various types of cancer, we conducted high-throughput screening and genome-wide association mapping using 680 lymphoblastoid cell lines from the 1000 Genomes Project. The drug treatments considered in this study represent nine drug classes widely used in the treatment of cancer in addition to the paclitaxel + epirubicin combination therapy commonly used for breast cancer patients. Our genome-wide association study (GWAS) found several significant and suggestive associations. We prioritized consistent associations for functional follow-up using gene-expression analyses. The NAD(P)H quinone dehydrogenase 1 (NQO1) gene was found to be associated with the dose-response of arsenic trioxide, erlotinib, trametinib, and a combination treatment of paclitaxel + epirubicin. NQO1 has previously been shown as a biomarker of epirubicin response, but our results reveal novel associations with these additional treatments. Baseline gene expression of NQO1 was positively correlated with response for 43 of the 44 treatments surveyed. By interrogating the functional mechanisms of this association, the results demonstrate differences in both baseline and drug-exposed induction.}, number={8}, journal={PLOS GENETICS}, publisher={Public Library of Science (PLoS)}, author={Akhtari, Farida S. and Green, Adrian J. and Small, George W. and Havener, Tammy M. and House, John S. and Roell, Kyle R. and Reif, David M. and McLeod, Howard L. and Wiltshire, Timothy and Motsinger-Reif, Alison A.}, editor={Vazquez, FranciscaEditor}, year={2021}, month={Aug} }
 @article{akhtari_havener_hertz_ash_larson_carey_mcleod_motsinger-reif_2021, title={Race and smoking status associated with paclitaxel drug response in patient-derived lymphoblastoid cell lines}, volume={31}, ISSN={["1744-6880"]}, DOI={10.1097/FPC.0000000000000419}, abstractNote={The use of ex-vivo model systems to provide a level of forecasting for in-vivo characteristics remains an important need for cancer therapeutics. The use of lymphoblastoid cell lines (LCLs) is an attractive approach for pharmacogenomics and toxicogenomics, due to their scalability, efficiency, and cost-effectiveness. There is little data on the impact of demographic or clinical covariates on LCL response to chemotherapy. Paclitaxel sensitivity was determined in LCLs from 93 breast cancer patients from the University of North Carolina Lineberger Comprehensive Cancer Center Breast Cancer Database to test for potential associations and/or confounders in paclitaxel dose-response assays. Measures of paclitaxel cell viability were associated with patient data included treatment regimens, cancer status, demographic and environmental variables, and clinical outcomes. We used multivariate analysis of variance to identify the in-vivo variables associated with ex-vivo dose-response. In this unique dataset that includes both in-vivo and ex-vivo data from breast cancer patients, race (P = 0.0049) and smoking status (P = 0.0050) were found to be significantly associated with ex-vivo dose-response in LCLs. Racial differences in clinical dose-response have been previously described, but the smoking association has not been reported. Our results indicate that in-vivo smoking status can influence ex-vivo dose-response in LCLs, and more precise measures of covariates may allow for more precise forecasting of clinical effect. In addition, understanding the mechanism by which exposure to smoking in-vivo effects ex-vivo dose-response in LCLs may open up new avenues in the quest for better therapeutic prediction.}, number={2}, journal={PHARMACOGENETICS AND GENOMICS}, author={Akhtari, Farida S. and Havener, Tammy M. and Hertz, Daniel L. and Ash, Jeremy and Larson, Alexandra and Carey, Lisa A. and McLeod, Howard L. and Motsinger-Reif, Alison A.}, year={2021}, month={Feb}, pages={48–52} }
 @article{menden_wang_mason_szalai_bulusu_guan_yu_kang_jeon_wolfinger_et al._2019, title={Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen}, volume={10}, ISSN={["2041-1723"]}, DOI={10.1038/s41467-019-09799-2}, abstractNote={Abstract}, journal={NATURE COMMUNICATIONS}, author={Menden, Michael P. and Wang, Dennis and Mason, Mike J. and Szalai, Bence and Bulusu, Krishna C. and Guan, Yuanfang and Yu, Thomas and Kang, Jaewoo and Jeon, Minji and Wolfinger, Russ and et al.}, year={2019}, month={Jun} }
 @article{chen_akhtari_wagner_suzuki_wiltshire_motsinger-reif_dumond_2018, title={Pharmacogenetic Analysis of the Model-Based Pharmacokinetics of Five Anti-HIV Drugs: How Does This Influence the Effect of Aging?}, volume={11}, ISSN={["1752-8062"]}, DOI={10.1111/cts.12525}, abstractNote={Abstract}, number={2}, journal={CTS-CLINICAL AND TRANSLATIONAL SCIENCE}, author={Chen, Jingxian and Akhtari, Farida S. and Wagner, Michael J. and Suzuki, Oscar and Wiltshire, Tim and Motsinger-Reif, Alison A. and Dumond, Julie B.}, year={2018}, month={Mar}, pages={226–236} }
 @article{akhtari_havener_fukudo_jack_mcleod_wiltshire_motsinger-reif_2018, title={The influence of Neanderthal alleles on cytotoxic response}, volume={6}, ISSN={["2167-8359"]}, DOI={10.7717/peerj.5691}, abstractNote={Various studies have shown that people of Eurasian origin contain traces of DNA inherited from interbreeding with Neanderthals. Recent studies have demonstrated that these Neanderthal variants influence a range of clinically important traits and diseases. Thus, understanding the genetic factors responsible for the variability in individual response to drug or chemical exposure is a key goal of pharmacogenomics and toxicogenomics, as dose responses are clinically and epidemiologically important traits. It is well established that ethnic and racial differences are important in dose response traits, but to our knowledge the influence of Neanderthal ancestry on response to xenobiotics is unknown. Towards this aim, we examined if Neanderthal ancestry plays a role in cytotoxic response to anti-cancer drugs and toxic environmental chemicals. We identified common Neanderthal variants in lymphoblastoid cell lines (LCLs) derived from the globally diverse 1000 Genomes Project and Caucasian cell lines from the Children’s Hospital of Oakland Research Institute. We analyzed the effects of these Neanderthal alleles on cytotoxic response to 29 anti-cancer drugs and 179 environmental chemicals at varying concentrations using genome-wide data. We identified and replicated single nucleotide polymorphisms (SNPs) from these association results, including a SNP in the SNORD-113 cluster. Our results also show that the Neanderthal alleles cumulatively lead to increased sensitivity to both the anti-cancer drugs and the environmental chemicals. Our results demonstrate the influence of Neanderthal ancestry-informative markers on cytotoxic response. These results could be important in identifying biomarkers for personalized medicine or in dissecting the underlying etiology of dose response traits.}, journal={PEERJ}, author={Akhtari, Farida S. and Havener, Tammy M. and Fukudo, Masahide and Jack, John R. and McLeod, Howard L. and Wiltshire, Tim and Motsinger-Reif, Alison A.}, year={2018}, month={Oct} }