Greater understanding of the underlying mechanisms of cancer is leading to development of novel targeted therapies tailored to individual patients. However, response to these therapies often results in tumor stasis. Consequently, the biologically relevant drug dose and early response to treatment are determined using indirect or invasive indicators. A noninvasive method of assessing drug delivery and molecular response at the target site is therefore critically needed. Our long-term goal is to develop and implement noninvasive magnetic resonance (MR)-based molecular imaging methods that can detect the action of and response to novel targeted cancer treatments. The goal of this application is to pre-clinically test and implement a direct, noninvasive, 19F MR spectroscopic marker of histone deacetylase (HDAC) activity, as a specific indicator of molecular response to HDAC inhibitors (HDACIs) in vivo. A secondary goal is to identify downstream metabolic biomarkers associated with HDAC inhibition. We propose to test the fluorinated lysine derivative Boc-Lys-TFA-OH (BIT). We have confirmed that BLT is cleaved in vitro by HDAC. From MR spectroscopy (MRS) studies of cell extracts we have also determined that intracellular BLT levels are significantly higher following HDACI-treatment and correlate with HDAC inhibition. Phosphocholine (PC) and total choline (tCho) levels are also higher in treated cell extracts. We therefore suggest that higher cellular BLT levels together with higher tCho levels can serve as molecular markers of HDAC inhibition. To implement this in vivo we propose:
Specific Aim 1. To confirm BLT as an MRS pharmacodynamic marker of HDAC inhibition. We will use perfused live cells to model the in vivo situation in which intracellular and extracellular BLT signals are indistinguishable. BLT levels will be monitored by high resolution MRS and correlated with HDAC activity in control and HDACI-treated cells.
Specific Aim 2. To monitor HDAC inhibition in tumors in vivo using magnetic resonance spectroscopic imaging. We will use localized 19F spectroscopic imaging to monitor BLT levels and 1H spectroscopic imaging to measure tCho levels in control and treated tumors. The MR data will be correlated with HDAC activity, downstream signaling and tumor size. Future translation of this method to the clinic will allow for noninvasive longitudinal localized monitoring of HDACI-treatment. By informing on drug delivery and molecular response to treatment, noninvasively and at the target site, this technique therefore promises to improve patient care. Relevance. HDACIs are novel anti-cancer agents currently in clinical trials with promising results. However, appropriate drug dose and early response are often difficult to assess. The goal of this work is to develop a noninvasive MRS-based imaging method for detecting response to HDACIs at the target site. The introduction of this method into clinical use will therefore translate into improved patient care. ? ? ?
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| Ross, James; Najjar, Amer M; Sankaranarayanapillai, Madhuri et al. (2008) Fatty acid synthase inhibition results in a magnetic resonance-detectable drop in phosphocholine. Mol Cancer Ther 7:2556-65 |
| Sankaranarayanapillai, Madhuri; Tong, William P; Yuan, Qing et al. (2008) Monitoring histone deacetylase inhibition in vivo: noninvasive magnetic resonance spectroscopy method. Mol Imaging 7:92-100 |
