Ras proteins are critically involved in transformation, proliferation, and survival of malignant cells, including blasts from patients with acute leukemia and myelodysplasia. Ras proteins require post-translational modification (prenylation) for activity, as do several other critical proteins. Prenylation involves addition of 15- (farnesyl) or 20-carbon (geranylgeranyl) groups, intermediates in de-novo cholesterol biosynthesis, to specific CAAX motifs near the C-terminus. Specific inhibitors of enzymes that catalyze prenylation, farnesyltransferase (FT) and geranylgeranyltransferase-l and -II (GGT-1, GGT-II), are currently in clinical trials or preclinical models. Efficacy of such inhibitors may be limited by the potential for some Ras proteins to be prenylated by either FT or GGT-1; inhibition of one enzyme may be circumvented by the other transferase. An alternative therapeutic strategy involves HGM-CoA reductase inhibitors (statins), such as atorvastatin, which block synthesis of both farnesyl and geranylgeranyl groups. Statins inhibit prenylation and proliferation of human leukemia, and other malignant, cell lines in-vitro. The long-range objective of our research is to determine the clinical utility of inhibiting prenylation in patients with acute leukemia, and myelodysplasia. The proposed investigations are an initial test of the hypothesis that atorvastatin inhibits Ras prenylation in malignant myeloblasts at clinically tolerable doses.
Two specific aims are proposed: (1.) To define the maximal tolerated dose, pharmacokinetics, and pharmacodymamics of atorvostatin in patients with acute leukemias or myelodysplasia, in an accelerated-titration phase-I trial; (2.) To determine whether inhibition of prenylation of prelamin A in buccal mucosa, a surrogate tissue, correlates with inhibition of Ras prenylation in leukemic cells. Pharmacodynamic endpoints in specific aim 1 include effects of atorvastatin on clinical / laboratory toxicities, Ras prenylation, HMG-CoA reductase activity, and mevalonate levels.
In specific aim 2, inhibition of prelamin A prenylation is compared against inhibition of prenylation in tumor tissue, as initial validation of the surrogate endpoint. The proposed investigations, the first clinical trial of atorvastatin in cancer patients, lay groundwork for subsequent proof-of-principle and phase II trials in cancer patients.
