TOP PGRN PUBLICATIONS The following publications from the Mayo PPII PGRN were not selected to be comprehensive, but rather to provide an overview – over a period of five years – of one facet of our work, studies of the pharmacogenomics of cancer treatment, including “endocrine therapy” , “chemotherapy” and “radiation therapy”. Gemcitabine metabolic pathway genetic polymorphisms and response in non-small cell lung cancer patients. Pharmacogenet. Genomics 22(2):105-16. (2012). Li, L., Schaid, D.J., Fridley, B.L., Kalari, K.R., Jenkins, G.D., Abo, R.P., Batzler, A., Moon, I., Pelleymounter, L., Eckloff, B.W., Wieben, E.D., Sun, Z., Pang, Y. and Wang, L. This paper describes the merger of the use of LCLs to identify and interpret genetic variation associated with a cellular phenotype, gemcitabine cytotoxicity, and the subsequent validation of these genetic variants using samples from pancreatic cancer patient treated with gemcitabine. This is one of the few examples that demonstrate the utility of the LCL model system and the use of this system to identify candidates that were also associated with clinical response in cancer patients. Glycine and a glycine dehydrogenase (GLDC) SNP as citalopram/escitalopram response biomarkers in depression: pharmacometabolomics-informed pharmacogenomics. Clin Pharmacol Ther. 89(1):97-104. (2011) Ji, Y., Hebbring, S., Zhu, H., Jenkins. G.D., Biernacka, J., Snyder, K., Drews, M., Fiehn, O., Zeng, Z., Schaid, D., Mrazek, D.A., Kaddurah-Daouk, R. and Weinshilboum, R.M. This paper describes the “merging” of pharmacometabolomic and pharmacogenomic data, i.e., “pharmacometabolomics-informed pharmacogenomics”, to discover and replicate SNPs in an unanticipated gene, GLDC, associated with SSRI response in depressed patients. This is one of the first examples of the use of metabolomics to complement and “guide” genomic studies of drug response. Genomics and drug response. NEJM 364 (12):1144-1153. (2011). Wang, L., McLeod, H.L. and Weinshilboum, R.M. We know that you prefer “peer reviewed” original research papers, but the fact that this review was invited for inclusion in the NEJM Tenth Anniversary of the Genome Project “Genomics in Medicine” series is an indication of the success of PGRN efforts to highlight pharmacogenomics as a leading edge in the application of genomic science to medicine. Functional genetic polymorphisms in the aromatase gene CYP19 vary the response of breast cancer patients to neoadjuvant therapy with aromatase inhibitors. Cancer Res. (2010) 70(1):319- 328 Wang, L., Ellsworth, K.A. Moon, I., Pelleymounter, L.L., Eckloff, B.W., Martin, Y.N., Fridley, B.L., Jenkins, G.D., Batzler, A., Suman, V.J., Ravi, S., Dixon, J.M., Miller, W.R., Wieben, E.D., Buzdar, A., Weinshilboum, R.M. and Ingle, J.N. This manuscript utilized tissue from Scottish women with breast cancer who were treated with aromatase inhibitors in the neoadjuvant setting. We sequenced the CYP19 gene tissue from these patients – which was also used to measure aromatase activity. Two linked CYP19 SNPs were found to be associated with response to aromatase inhibitors and, in a replication study, they were also associated with circulating levels of estrogen. Genome-wide associations and functional genomic studies of musculoskeletal adverse events in women receiving aromatase inhibitors. J. Clin. Oncol. (2010) Nov1; 28(31):4674-82.Ingle, J.N., Schaid, D.J., Goss, P.E., Liu, M., Mushiroda, T., Chapman, J.-A., Kubo, M., Jenkins, G.D., Batzler, A., Shepherd, L., Pater, J., Wang, L., Ellis, M.J., Stearns, V., Rohrer, D., Goetz, M.P., Pritchard, K.I., Flockhart, D.A., Nakamura, Y. and Weinshilboum, R.M. This manuscript pursues the topic addressed in manuscripts (1) i.e., endocrine therapy of breast cancer and the important role of aromatase inhibitors (AIs). A major adverse response to these agents is severe musculoskeletal pain. This GWAS used DNA from the largest current AI study of breast cancer and identified the relationship of the TCL1A gene to this adverse response, based both on GWAS data and the results of extensive functional genomic studies. Radiation Pharmacogenomics: A genome wide association approach to identify radiation response biomarkers using human lymphoblastoid cell lines. Genome Res. (2010) Nov(20)11:1482-92. Niu N, Qin Y, Fridley BL, Hou J, Kalari KR, Zhu M, Wu TY, Jenkins GD, Batzler A, Wang L. This manuscript used the same cell line system as described in article (2) to attempt to identify genetic variations/ genes that might contribute to radiation response. The study has identified 5 candidate genes which showed effect on radiation sensitivity after knockdown in various cancer cell lines. Those candidates would be potential biomarkers for radiation response and would also provide novel mechanistic insights into the biology underlying radio-sensitivity and radio-resistance. FKBP51 acts as a scaffolding protein to regulate Akt phosphorylation. Cancer Cell (2009) 16(3):259-66 Pei, H., Li, L., Fridley, B., Jenkins, G., Kalari, R., Lingle, W., Petersen, G., Lou, Z. and Wang, L.
This mechanistic follow-up of the preceding manuscript demonstrated that FKBP5 encodes a scaffolding protein that “links” a phosphatase to AKT, a mechanism that plays a role in variation in response to a series of cytotoxic antineoplastic agents including gemcitabine, taxanes and irinotecan. Gemcitabine and cytosine arabinoside cytotoxicity: association with lymphoblastoid cell expression. Cancer Res. (2008) 68(17):7050-7058. Li, L., Fridley, B.L., Kalari, K.R., Jenkins, G.D., Batzler, A., Safgren, S.L., Hildebrandt, M.A.T., Ames, M.M., Schaid, D.J. and Wang, L.
This manuscript describes the use of a cell line-based model system consisting of data-rich lymphoblastoid cell lines. In this study, expression array data were used to identify, and functionally validate, novel candidate genes, NT5C3 and FKBP5, associated with response to the solid tumor antineoplastic drug gemcitabine. This work led directly to basic mechanistic studies of FKBP5 which are described in the following manuscript.
Nuklearmedizin Westend – Dr. med. R. Jochens – Dr. med. B. Kettner – PD Dr. med. W.S. Richter Spandauer Damm 130 / Haus 9 – 14050 Berlin – Telefon 030/ 3069940 Myokardszintigraphie Liebe Patientin, lieber Patient! Ihre behandelnde Ärztin / Ihr behandelnder Arzt hält es auf Grund der bisherigen Untersuchungs- ergebnisse für not wendig, eine weiterführende nuklearmedizinisc
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) December 2000 Additional copies are available from: Office of Training and Communications Division of Communications Management (Internet) http://www.fda.gov/cder/guidance/index.htm Office of Communication