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:  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); To provide stable isotope dilution LC/MS methodology for the analysis of hydroxyandrogens in identical biological matrices;and  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.
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.
|Beshiri, Michael L; Tice, Caitlin M; Tran, Crystal et al. (2018) A PDX/Organoid Biobank of Advanced Prostate Cancers Captures Genomic and Phenotypic Heterogeneity for Disease Modeling and Therapeutic Screening. Clin Cancer Res 24:4332-4345|
|Russo, Joshua W; Liu, Xiaming; Ye, Huihui et al. (2018) Phosphorylation of androgen receptor serine 81 is associated with its reactivation in castration-resistant prostate cancer. Cancer Lett 438:97-104|
|Mostaghel, Elahe A (2018) Alternative Acts: Oncogenic Splicing of Steroidogenic Enzymes in Prostate Cancer. Clin Cancer Res :|
|Uo, Takuma; Plymate, Stephen R; Sprenger, Cynthia C (2018) The potential of AR-V7 as a therapeutic target. Expert Opin Ther Targets 22:201-216|
|Arai, Seiji; Jonas, Oliver; Whitman, Matthew A et al. (2018) Tyrosine Kinase Inhibitors Increase MCL1 Degradation and in Combination with BCLXL/BCL2 Inhibitors Drive Prostate Cancer Apoptosis. Clin Cancer Res 24:5458-5470|
|Viswanathan, Srinivas R; Ha, Gavin; Hoff, Andreas M et al. (2018) Structural Alterations Driving Castration-Resistant Prostate Cancer Revealed by Linked-Read Genome Sequencing. Cell 174:433-447.e19|
|Russo, Joshua W; Gao, Ce; Bhasin, Swati S et al. (2018) Downregulation of Dipeptidyl Peptidase 4 Accelerates Progression to Castration-Resistant Prostate Cancer. Cancer Res 78:6354-6362|
|Sowalsky, Adam G; Ye, Huihui; Bhasin, Manoj et al. (2018) Neoadjuvant-Intensive Androgen Deprivation Therapy Selects for Prostate Tumor Foci with Diverse Subclonal Oncogenic Alterations. Cancer Res 78:4716-4730|
|Zhu, Yezi; Sharp, Adam; Anderson, Courtney M et al. (2018) Novel Junction-specific and Quantifiable In Situ Detection of AR-V7 and its Clinical Correlates in Metastatic Castration-resistant Prostate Cancer. Eur Urol 73:727-735|
|Penning, Trevor M (2018) Dehydroepiandrosterone (DHEA)-SO4 Depot and Castration-Resistant Prostate Cancer. Vitam Horm 108:309-331|
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