The cytidine analogue gemcitabine is first line chemotherapy for the treatment of pancreatic cancer, and it has also shown promising results in the treatment of breast cancer and non-small cell lung cancer. Gemcitabine has its effect as a result of a """"""""pathway"""""""" that includes drug transporters, enzymes catalyzing drug activation and inactivation, and drug targets. However, very little is known with regard to determinants of variation in gemcitabine response, especially single nucleotide polymorphisms (SNPs) in genes outside of the pathway described by our current knowledge of this drug. In order to identify additional genes of importance for variation in gemcitabine response, we have used 300 Human Variation Panel lymphoblastoid cell line as a model system for common genetic variation to perform genome-wide expression association studies to identify genes with expression levels that were significantly associated with variation in gemcitabine cytotoxicity (IC50 values). One top candidate gene, FKBP5, a gene encoding a 51 kDa immunophilin, was shown to affect the apoptotic pathway in response to gemcitabine. Specifically, lower expression of FKBP5 was associated with resistance to gemcitabine-induced cytotoxicity. We also demonstrated an inhibitory role for FKBP5 in AKT phosphorylation. As a result, we hypothesize that FKBP5 affects gemcitabine response by negatively regulating AKT activation and that genetic variation associated with FKBP5 gene expression and protein function might contribute significantly to variation in gemcitabine response. In this application, we propose to determine mechanisms by which FKBP5 regulates AKT activation, followed by testing the role of FKBP5 in gemcitabine response using mice models and tumor samples from pancreatic cancer patients treated with gemcitabine. In addition, we will also determine gene sequence variation that is associated with FKBP5 gene expression and response to gemcitabine using 300 lymphoblastoid cell lines, followed by performing functional genomic studies with these SNPs. Finally, we will perform a genotype-phenotype correlation study with DNA from pancreatic cancer patients to determine whether SNPs that affect FKBP5 expression and/or protein function might influence response to gemcitabine when used to treat pancreatic cancer. In summary, this comprehensive series of experiments will enhance our understanding of mechanisms of gemcitabine resistance and may identify biomarkers that might help predict gemcitabine response in the treatment of pancreatic cancer.
The cytidine analogue gemcitabine is first line chemotherapy for the treatment of pancreatic cancer. However, very little is known with regard to determinants of variation in gemcitabine response, especially single nucleotide polymorphisms (SNPs) in genes outside of the """"""""pathway"""""""" described by our current knowledge of the metabolism and """"""""targets"""""""" for this drug. In order to identify additional genes of importance for variation in gemcitabine response, we have used 300 Human Variation Panel lymphoblastoid cell lines as a model system, together with genome-wide approaches to identify one top candidate gene, FKBP5, for which expression was significantly associated with gemcitabine sensitivity. In this application, based on extensive preliminary data, we propose to investigate mechanisms by which FKBP5 regulates response to gemcitabine and to identify genetic variation in FKBP5 that might be used as a biomarker to help predict gemcitabine response in the treatment of pancreatic cancer.
|Cairns, Junmei; Fridley, Brooke L; Jenkins, Gregory D et al. (2018) Differential roles of ERRFI1 in EGFR and AKT pathway regulation affect cancer proliferation. EMBO Rep 19:|
|Hanson, Casey; Cairns, Junmei; Wang, Liewei et al. (2018) Principled multi-omic analysis reveals gene regulatory mechanisms of phenotype variation. Genome Res 28:1207-1216|
|Ho, Ming-Fen; Lummertz da Rocha, Edroaldo; Zhang, Cheng et al. (2018) TCL1A, a Novel Transcription Factor and a Coregulator of Nuclear Factor ?B p65: Single Nucleotide Polymorphism and Estrogen Dependence. J Pharmacol Exp Ther 365:700-710|
|Ho, Ming-Fen; Correia, Cristina; Ingle, James N et al. (2018) Ketamine and ketamine metabolites as novel estrogen receptor ligands: Induction of cytochrome P450 and AMPA glutamate receptor gene expression. Biochem Pharmacol 152:279-292|
|Dudenkov, Tanda M; Ingle, James N; Buzdar, Aman U et al. (2017) SLCO1B1 polymorphisms and plasma estrone conjugates in postmenopausal women with ER+ breast cancer: genome-wide association studies of the estrone pathway. Breast Cancer Res Treat 164:189-199|
|Takahashi, Paul Y; Ryu, Euijung; Pathak, Jyotishman et al. (2017) Increased risk of hospitalization for ultrarapid metabolizers of cytochrome P450 2D6. Pharmgenomics Pers Med 10:39-47|
|Safarova, Maya S; Klee, Eric W; Baudhuin, Linnea M et al. (2017) Variability in assigning pathogenicity to incidental findings: insights from LDLR sequence linked to the electronic health record in 1013 individuals. Eur J Hum Genet 25:410-415|
|Bielinski, S J; St Sauver, J L; Olson, J E et al. (2017) Are patients willing to incur out-of-pocket costs for pharmacogenomic testing? Pharmacogenomics J 17:1-3|
|Ho, Ming-Fen; Weinshilboum, Richard M (2017) Immune Mediator Pharmacogenomics: TCL1A SNPs and Estrogen-Dependent Regulation of Inflammation. J Nat Sci 3:|
|St Sauver, Jennifer L; Olson, Janet E; Roger, Veronique L et al. (2017) CYP2D6 phenotypes are associated with adverse outcomes related to opioid medications. Pharmgenomics Pers Med 10:217-227|
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