Sabrina M. Ronen, Ph.D. sabrina.ronen@radiology.ucsf.edu Associate Professor of Radiology University of California, San Francisco

Research Program

The goal of research performed in my laboratory is to develop, validate and implement robust noninvasive magnetic resonance (MR)–based methodologies that can be used: (1) to detect oncogenic mutations that lead to onset and progression of cancer; and (2) to monitor response to traditional chemotherapies and novel molecular targeted therapies. Our work focuses on preclinical cell and xenograft models and uses multinuclear 31P, 1H, 13C, hyperpolarized 13C and 19F MR spectroscopy (MRS) and MR imaging (MRI) as well as complementary biological, biochemical and molecular biological techniques. Our studies result in validated MR biomarkers of transformation and response to treatment that can be translated to patients in vivo.

Specific areas of research

(1) Monitoring HDAC activity and inhibition in breast and prostate cancer. The goal of this study is to pre-clinically test and implement a noninvasive 19F-MR spectroscopic imaging agent that reports on HDAC inhibition. A secondary goal is to identify downstream metabolic biomarkers associated with response to HDAC inhibitors.

(2) Monitoring PDGFR expression and activity in prostate bone metastases. The goal of this study is to develop and test MRI-based methods for assessing (1) PDGFR expression and (2) PDGFR activity, in a model of prostate cancer bone metastases.

(3) Identifying MRS metabolomic biomarkers of glioma. The goal of this study is to investigate the link between gene expression and the MRS-based metabolic profiles of brain tumors.

(4) Investigating modulation of choline metabolism by signaling via the RAS, MAPK and PI3K pathways. The goal of this study is to determine the mechanisms by which signaling pathways affect cellular metabolism resulting in modulation of PC and other choline-containing metabolites.

Current Grants

Idea Development Award PC060032 (U.S. Department of Defense)
Molecular and Functional Magnetic Resonance Imaging of Vasculature and PDGFR-expressing Neovasculature and Tumor in Prostate Cancer Bone Metastases

Prostate cancer is the most frequently diagnosed cancer in men and the occurrence of metastases that are resistant to therapy makes prostate cancer the second leading cause of male cancer deaths. An increasing understanding of the biology of cancer is leading to the development of novel therapies with therapeutic targets expanding beyond the tumor cell to include the altered characteristics of non-malignant cells in the tumor stroma both at the primary and the metastatic sites. In this context PDGF signaling has been shown to pay a physiological role in a number of processes that lead to the development of prostate cancer metastases. However, to date, no noninvasive methods are available to inform on PDGFR status. We propose that PDGFR-targeted macromolecular dynamic contrast enhanced MRI (DCE-MRI) could inform on PDGFR expression while un-targeted macromolecular DCE-MRI could inform on PDGFR activity in a noninvasive and specific way. The purpose of this project is to develop and validate these methods by: (1) developing targeted and non-targeted contrast materials; and (2) using these materials and DCE-MRI to assess PDGFR expression and activity in prostate cancer bone metastases models with defined PDGF and PDGFR status.

Related Articles

Dafni H, Kim S-J, Bankson JA, Sankaranarayanapillai M, Ronen SM. Macromolecular DCE-MRI detects reduced vascular permeability in a prostate cancer bone metastasis model following anti-PDGFR therapy, indicating a drop in VEGFR activation. Magnetic Resonance in Medicine, in press.

R21 CA120010 (NIH)
Non-invasive Molecular MR Spectroscopic Imaging of Histone Deacetylase Activity

The goal of this work is to pre-clinically test and implement a direct, noninvasive, 19F MR spectroscopic marker of histone deacetylase (HDAC) activity in vivo, namely the fluorinated HDAC substrate Boc-Lys-Tfa-OH (BLT), as a specific indicator of molecular response to HDAC inhibitors (HDACIs). A secondary goal is to identify downstream metabolic biomarkers associated with HDAC inhibition. We have determined that BLT is cleaved in vitro by recombinant HDAC. In cells we have found that intracellular BLT levels, as observed by 19F MRS of extracts, are significantly higher following HDACI-treatment and correlate with HDAC inhibition. Phosphocholine (PC) and total choline levels (tCho) are also higher in treated cells. We therefore hypothesize that higher cellular BLT levels together with higher tCho levels can serve as markers of HDAC inhibition. To implement this in vivo we propose: Specific Aim 1. To assess BLT as an MRS pharmacodynamic marker of HDAC inhibition in cells. Specific Aim 2. To monitor HDAC inhibition in tumors in vivo using magnetic resonance spectroscopic imaging. The MR data will be correlated with HDAC activity, downstream signaling and response. In the clinical setting this method will allow for longitudinal studies of HDACI-treatment in patients generating both spatial and temporal information. This noninvasive technique therefore promises to improve patient care by providing information regarding drug delivery and response to treatment.

Related Articles

Sankaranarayanapillai M, Tong W, Maxwell D, Pal A, Pang J, Bornmann W, Gelovani J, Ronen SM. Detection of Histone Deacetylase Inhibition by Noninvasive Magnetic Resonance Spectroscopy. Mol Cancer Ther, 5(5):1325-34, 2006.

Sankaranarayanapillai M, Tong W, Yuan Q, Bankson J, Dafni H, Bornmann W, Soghomonyan S, Pal A, Ramirez M, Webb D, Kaluarachchi K, Gelovani J, Ronen SM. Monitoring histone deacetylase inhibition in vivo: a noninvasive magnetic resonance spectroscopy method. Molecular Imaging, in press.

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