Elucidating Mechanisms of Farnesyltransferase Inhibitor Action and Resistance in Breast Cancer by Bioluminescence Imaging
Abstract
Farnesyltransferase inhibitors (FTIs) block the post-translational processing of signaling proteins, such as Ras, that have key roles in breast cancer biology. In phase II trials, FTIs have exhibited clinical benefit toward a subset of breast cancer patients. However, FTIs have yet to be used widely in breast cancer therapy because it is not yet possible to identify patients likely to be FTI-sensitive or to use combinatorial therapy to broaden the spectrum of patients that respond to FTIs. To overcome these hurdles, mechanisms determining whether breast cancer tumors are FTI-sensitive or -resistant in vivo must be understood. Accordingly, this recently funded project is developing molecular imaging strategies that for the first time specifically detect the ability of FTIs to inhibit farnesylation in tumors of living animals. Our initial proposed imaging strategy uses chimeric transcription factors fused to the prenylation domains H-Ras or Cdc42, which localize to the nucleus upon inhibition of prenylation. When unprenylated, the fusion chimeras bind their cognate promoter, driving expression of firefly luciferase, a reporter that can be readily imaged in cells and animals with an ultrasensitive, cooled CCD camera. This strategy should offer the opportunity to visualize over time the action of FTIs and GGTIs toward specific, biologically relevant prenylation-dependent proteins in tumors of living animals.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2008
- Accession Number
- ADA491469
Entities
People
- David Piwnica-Worms
- Ken Blumer
Organizations
- Washington University in St. Louis