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[Farnesyltransferase inhibitors: preliminary results in acute myeloid leukemia]
Xavier Thomas1, Mohamed Elhamri
1Service d'hématologie, hôpital Edouard-Herriot, 5, place Arsonval, 69437 Lyon Cedex 03. xavier.thomas@chu-lyon.fr
Abstract:
Farnesyltransferase inhibitors (FTIs) are small-molecule inhibitors that selectivly inhibit farnesylation of a number of intracellular substrate proteins such as Ras. Preclinical work has revealed their ability to effectively inhibit tumor growth in vitro and in vivo in animal models across a wide range of malignant phenotypes. Acute myeloid leukemias (AMLs) are appropriate disease targets in that they express relevant biologic targets such as Ras, MEK, AKT, and others that may depend upon farnesyl protein transferase activity to promote cell proliferation and survival. Indeed, different intracellular proteins are substrates for prenylation. Interruption of prenylation may prevent substrates from undergoing maturation which may result in the inhibition of cellular events that depend on the function of those substrates. Phase I trials in AML and myelodysplasia have demonstrated biologic and clinical activities as determined by target enzyme inhibition, low toxicity, and both complete and partial responses. As a result, phase II trials have been initiated in order to further validate clinical activity and to identify downstream signal transduction targets that may be modified by these agents. It is anticipated that these studies will serve to define the optimal roles of FTIs in patients with these hematologic malignancies and provide insight into effective methods by which to combine FTIs with other agents.
Insights
Farnesyltransferase inhibitors (FTIs) show promise in treating acute myeloid leukemia (AML) by blocking cancer cell growth. Early trials indicate low toxicity and positive clinical responses, warranting further investigation in Phase II studies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Farnesyltransferase inhibitors (FTIs) target intracellular protein farnesylation, a process crucial for the function of proteins like Ras.
- Preclinical studies demonstrate FTIs effectively inhibit tumor growth across various malignant phenotypes in vitro and in vivo.
- Acute myeloid leukemias (AMLs) are suitable targets due to the expression of proteins such as Ras, MEK, and AKT, which rely on farnesyl protein transferase activity.
Purpose of the Study:
- To evaluate the clinical activity and safety of FTIs in patients with AML and myelodysplasia.
- To identify downstream signal transduction targets affected by FTI treatment.
- To define the optimal role of FTIs in hematologic malignancies and explore combination therapies.
Main Methods:
- Phase I clinical trials were conducted to assess biologic and clinical activities, including target enzyme inhibition and toxicity.
- Phase II trials were initiated to further validate clinical activity and explore downstream signaling pathways.
- Studies involved patients with AML and myelodysplasia.
Main Results:
- Phase I trials demonstrated significant biologic activity, characterized by target enzyme inhibition and low toxicity.
- Clinical responses, including complete and partial responses, were observed in Phase I trials.
- FTIs showed the ability to inhibit tumor growth in preclinical models.
Conclusions:
- FTIs exhibit promising biologic and clinical activity in AML and myelodysplasia.
- Further Phase II trials are necessary to confirm efficacy and elucidate mechanisms of action.
- FTIs may play a significant role in treating hematologic malignancies, potentially in combination with other agents.
