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[Farnesyl transferase inhibitors: one target may be found in another]
Julien Mazières1, Anne Pradines, Gilles Favre
1Inserm U.563, Centre de Physiopathologie Toulouse Purpan, Département Innovation Thérapeutique et Oncologie Moléculaire, Institut Claudius Regaud, 20-24, rue du pont Saint-Pierre, 31052 Toulouse, France. maziere@icr.fnclcc.fr
Abstract:
The fact that proteins such as Ras require farnesylation to induce malignant transformation prompted many investigators to design farnesyl transferase inhibitors (FTI) as novel anticancer drugs. FTIs inhibit the growth of ras transformed cells in vitro and induce tumor regression in ras dependent tumor in vivo. Moreover, FTIs inhibit tumor progression in human tumor xenograft models. Currently, FTIs are undergoing phase I and II trials in various cancer types. They show impressive antitumour efficacy and they lack toxicity. Despite these promising results, the development of such molecules in hindered by the absence of appropriate clinical endpoints and of surrogate biological markers. Indeed, it seems likely that Ras is not the critical target of FTIs and that inhibition of the farnesylation of proteins such as RhoB, might also contribute to the observed antitumour properties. Identification of targets that underlie their biological effect is essential in order to predict and evaluate their efficacy.
Insights
Farnesyl transferase inhibitors (FTIs) show promise as anticancer drugs by inhibiting tumor growth and progression. Further research is needed to identify specific molecular targets for optimal efficacy and clinical application.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Context:
- Ras proteins require farnesylation for malignant transformation.
- Farnesyl transferase inhibitors (FTIs) were developed as novel anticancer agents.
- FTIs demonstrate efficacy in preclinical cancer models.
Purpose:
- To evaluate the efficacy of FTIs in inhibiting cancer cell growth and tumor progression.
- To explore the potential of FTIs in clinical trials for various cancer types.
- To address challenges in FTI development, including the need for clinical endpoints and biomarkers.
Summary:
- FTIs inhibit the growth of ras-transformed cells in vitro and induce regression of ras-dependent tumors in vivo.
- Preclinical studies show FTIs inhibit tumor progression in human tumor xenograft models.
- FTIs are currently in Phase I and II clinical trials, exhibiting significant antitumor efficacy with low toxicity.
Impact:
- FTIs represent a promising class of anticancer drugs with demonstrated efficacy and safety.
- The development of FTIs is hampered by the lack of clear clinical endpoints and validated surrogate biomarkers.
- Identifying the precise molecular targets of FTIs, potentially including proteins like RhoB beyond Ras, is crucial for predicting and evaluating treatment efficacy.