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Accession Number:
ADA455297
Title:
Studies of a RAS Antagonist in Breast Cancer
Descriptive Note:
Final rept. 8 Apr 2002-7 Apr 2006
Corporate Author:
VIRGINIA UNIV CHARLOTTESVILLE
Report Date:
2006-05-01
Pagination or Media Count:
24.0
Abstract:
Deprivation of estrogen, called Endocrine Therapy ET, is commonly used to treat women with estrogen receptor ER positive breast cancer. Resistance to ET occurs in many women after about 18 months of treatment. Upregulation of growth factor pathways mediated by the 21 kD RasGTPase protein may contribute to resistance to ET. A novel Ras antagonist, farnesylthiosalicylate FTS causes Ras downreguation with concomitant abrogation of growth factor pathways. We tested the ability of FTS, which was complexed to a cyclodextrin moiety for solubility, to reduce the growth of ER positive breast cancer cells that were resistant to ET. FTS prevented growth of ER positive cells by increasing apoptosis and reducing proliferation. Surprisingly the FTS enhanced apoptosis in breast cancer cells was synergistic with the effects of estradiol. Accompanying loss of cell growth was a significant reduction in the response to estrogen. Of major interest was the unexpected observation that FTS blocked the signaling molecule, mTOR via a novel mechanism, the dissociation of RAPTOR from mTOR. In vivo studies have demonstrated a reduction in tumor size with FTS at doses that caused no demonstrable toxicity. We suggest that FTS should enter preclinical trials against ER positive breast cancer.
Distribution Statement:
APPROVED FOR PUBLIC RELEASE
