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Farnesyltransferase inhibitors
S M Hahn1, E Bernhard, W G McKenna
1Department of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA 19104-4283, USA.
Abstract:
The targeting of molecular abnormalities in neoplasms may provide an opportunity to improve the selectivity of cancer therapy. Ras mutations are a common genetic event in human cancers. Other genetic changes in tumors can signal through ras-dependent pathways as well. The targeting of ras through the inhibition of Ras protein farnesylation is one new cancer treatment strategy under clinical evaluation. Several farnesyltransferase inhibitors (FTIs) have been evaluated in phase I trials. The toxicity and maximally tolerated doses of several FTIs have been determined, and clinical trials are underway to evaluate FTIs in combination with conventional cytotoxic chemotherapy agents. Also underway are attempts to develop assays to measure the biological effects of the FTI in patients. Inhibition of farnesylation of a number of surrogate markers are currently being investigated. These efforts may provide insight into the mechanism of action of these compounds and lead to improved patient selection for clinical trials.
Insights
Targeting Ras protein farnesylation with farnesyltransferase inhibitors (FTIs) is a novel cancer therapy strategy. Clinical trials are evaluating FTIs for improved cancer treatment selectivity and patient selection.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Targeting molecular abnormalities in neoplasms can enhance cancer therapy selectivity.
- Ras mutations are frequent in human cancers, and other genetic changes can activate ras-dependent pathways.
- Inhibiting Ras protein farnesylation is an emerging cancer treatment strategy.
Purpose of the Study:
- To evaluate farnesyltransferase inhibitors (FTIs) as a novel cancer treatment strategy.
- To determine the toxicity and maximally tolerated doses of FTIs.
- To develop assays for measuring FTI biological effects and improve patient selection.
Main Methods:
- Clinical evaluation of several FTIs in Phase I trials.
- Assessment of FTI toxicity and maximally tolerated doses.
- Investigation of surrogate markers for farnesylation inhibition.
Main Results:
- Several FTIs have undergone Phase I clinical trials.
- Toxicity and maximally tolerated doses for multiple FTIs have been established.
- Ongoing research focuses on developing assays to measure biological effects.
Conclusions:
- Farnesyltransferase inhibitors represent a promising targeted cancer therapy.
- Further research is needed to elucidate FTI mechanisms of action and optimize patient selection for clinical trials.