The Steroid Analytical Core will provide sophisticated analytical methodologies for measuring the androgen metabolome with sufficient sensitivity and selectivity in different biological matrices for all Projects in the Program, for the Administrative/Clinical/Biostatistics Core A and for the Biospecimen/Animal Model Facility Core B. These matrices include medium from prostate cancer lines maintained in culture, xenograft models of castrate resistant prostate cancer (CRPC), and serum from their immunodeficient murine hosts. Ultimately, these methods can be applied to patient specimens (serum, prostate and bone biopsies) to determine the efficacy of different androgen ablative therapies in CRPC, and to help identify mechanisms of resistance to these therapies. Stable-isotope dilution liquid chromatography-mass spectrometry (LC/MS) of androgens and their precursor pregnanes will be the methodology employed. The LC/MS assays developed and provided in this core will be unique since no existing assays with sufficient sensitivity and selectivity are currently available to detect and quantitate all the steroids of interest. A unique resource of the Steroid Analytical Core is access to a panel of recombinant ketosteroid reductases (aldo-keto reductases) that can be used as synthons to generate the required [13C]-labeled internal standards. The Steroid Analytical Core will provide access to state-of-the art instrumentation and methods that will be cost-effective to measure steroid levels (androgens and pregnanes) not routinely available in the laboratories of individual investigators. It will assist investigators in the design of their experiments so that they are compatible with the analytical tools available.
The specific aims of the Core are as follows: [1] To provide stable isotope dilution LC/MS methodology for the analysis of ketoandrogens in a variety of biological matrices (e.g. serum, cell culture, prostate tissue, and prostate and bone biopsies);[2] To provide stable isotope dilution LC/MS methodology for the analysis of hydroxyandrogens in identical biological matrices;and [3] To provide stable isotope dilution LC/MS methodology for the analysis of pregnane precursors of androgens in identical biological matrices. Since these methods are not routinely available elsewhere the Steroid Analytical Core will have an impact on prostate cancer research beyond this P01.

Public Health Relevance

Androgen deprivation therapy (ADT) of disseminated prostate cancer leads to castrate resistant prostate cancer (CRPC). Sensitive LC/MS methods will be developed in the Steroid Analytical Core to measure the androgen metabolome to elucidate mechanisms that drive CRPC and its resistance to therapy. The outcome of these measurements could lead to personalized ADT.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA163227-02
Application #
8765219
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
2
Fiscal Year
2014
Total Cost
$279,324
Indirect Cost
$30,937
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Damodarasamy, Mamatha; Vernon, Robert B; Chan, Christina K et al. (2015) Hyaluronan in aged collagen matrix increases prostate epithelial cell proliferation. In Vitro Cell Dev Biol Anim 51:50-8
Chen, Eddy J; Sowalsky, Adam G; Gao, Shuai et al. (2015) Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors. Clin Cancer Res 21:1273-80
Sowalsky, Adam G; Xia, Zheng; Wang, Liguo et al. (2015) Whole transcriptome sequencing reveals extensive unspliced mRNA in metastatic castration-resistant prostate cancer. Mol Cancer Res 13:98-106
Tamae, Daniel; Mostaghel, Elahe; Montgomery, Bruce et al. (2015) The DHEA-sulfate depot following P450c17 inhibition supports the case for AKR1C3 inhibition in high risk localized and advanced castration resistant prostate cancer. Chem Biol Interact 234:332-8
Jehle, Katja; Cato, Laura; Neeb, Antje et al. (2014) Coregulator control of androgen receptor action by a novel nuclear receptor-binding motif. J Biol Chem 289:8839-51
Hsieh, Chen-Lin; Fei, Teng; Chen, Yiwen et al. (2014) Enhancer RNAs participate in androgen receptor-driven looping that selectively enhances gene activation. Proc Natl Acad Sci U S A 111:7319-24
Cao, Bo; Qi, Yanfeng; Zhang, Guanyi et al. (2014) Androgen receptor splice variants activating the full-length receptor in mediating resistance to androgen-directed therapy. Oncotarget 5:1646-56
He, Housheng Hansen; Meyer, Clifford A; Hu, Sheng'en Shawn et al. (2014) Refined DNase-seq protocol and data analysis reveals intrinsic bias in transcription factor footprint identification. Nat Methods 11:73-8
Penning, Trevor M (2014) Androgen biosynthesis in castration-resistant prostate cancer. Endocr Relat Cancer 21:T67-78
Thadani-Mulero, Maria; Portella, Luigi; Sun, Shihua et al. (2014) Androgen receptor splice variants determine taxane sensitivity in prostate cancer. Cancer Res 74:2270-82

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