SABRINA RONEN - Associate Professor in Residence

Why UCSF? "My decision to move to UCSF (September 2007) was very easy. I already knew that the Surbeck Laboratory was a world leader in magnetic resonance research. I was familiar with the exceptional research being done here: spectroscopic imaging in brain and prostate cancer patients, which providing unique information to improve patient diagnosis, treatment and survival; development and implementation of novel hyperpolarized carbon techniques informing us on disease status; identification of new disease biomarkers, and more. However, when I visited UCSF it became clear that in addition to being a center of scientific excellence, UCSF also provides a highly collaborative and inter-disciplinary research environment. My own research is focused on developing and validating MR metabolomic biomarkers of cancer progression and response to treatment using pre-clinical models. As a member of the Surbeck lab, as well as the Program in Bioengineering, the Department of Radiology and Biomedical Imaging, the QB3 Institute, and the Cancer Center at UCSF, I now have the opportunity to interact and collaborate with leaders in MR research, basic cancer research, quantitative biology, oncology, and much more. In summary UCSF provides an outstanding scientific environment for performing world class research that can be directly translated to the clinic, resulting in improved patient care. Deciding to move to UCSF and become part of this extraordinary complex of people and programs was, therefore, an easy decision to make."

Abstract

Histone deacetylase (HDAC) inhibitors are new and promising antineoplastic agents. Current methods for monitoring early response rely on invasive biopsies or indirect blood-derived markers. Our goal was to develop a magnetic resonance spectroscopy (MRS)–based method to detect HDAC inhibition. The fluorinated lysine derivative Boc-Lys-(Tfa)-OH (BLT) was investigated as a ¹⁹F MRS molecular marker of HDAC activity together with ³¹P MRS of endogenous metabolites. In silico modeling of the BLTHDAC interaction and in vitro MRS studies of BLT cleavage by HDAC confirmed BLT as a HDAC substrate. BLT did not affect cell viability or HDAC activity in PC3 prostate cancer cells. PC3 cells were treated, in the presence of BLT, with the HDAC inhibitor p-fluorosuberoylanilide hydroxamic acid (FSAHA) over the range of 0 to 10 μmol/L, and HDAC activity and MRS spectra were monitored. Following FSAHA treatment, HDAC activity dropped, reaching 53% of control at 10 μmol/L FSAHA. In parallel, a steady increase in intracellular BLT from 14 to 32 fmol/cell was observed.BLT levels negatively correlated with HDAC activity consistent with higher levels of uncleaved BLT in cells with inhibited HDAC.Phosphocholine, detected by ³¹P MRS, increased from 7 to 16 fmol/cell following treatment with FSAHA and also negatively correlated with HDAC activity. Increased phosphocholine is probably due to heat shock protein 90 inhibition as indicated by depletion of client proteins. In summary, ¹⁹F MRS of BLT, combined with ³¹P MRS, can be used to monitor HDAC activity in cells.In principle, this could be applied in vivo to noninvasively monitor HDAC activity.[Mol Cancer Ther 2006;5(5):1325–34]

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