Chemoresistance remains a major impediment to curing leukemias and other cancers. We have discovered in acute myeloid leukemia (AML) cholesterol-mediated drug resistance that may provide targets for new, more effective therapies. We have shown that cholesterol levels commonly increase in AMI cells exposed in vitro to standard chemotherapeutics, and that many AMLs are chemosensitized when cholesterol synthesis is prohibited by co-treatments with mevalonate pathway inhibitors (statins). Cholesterol increments also occur in AML cells when xenografted mice are exposed to parenteral chemotherapy. However, normal bone marrow cells do not typically make adaptive cholesterol responses, and are relatively statin-insensitive. These data and other findings suggest that AMLs are abnormally dependent on cholesterol for their survival, and that statin co-administration will improve the efficacy of standard anti-leukemia regimens. Safe and effective statin doses have been identified for hypercholesterolemia indications, and our retrospective analyses showed that co-administration of statins at these conventional doses does not increase therapy-related toxicities in AML patients treated with standard chemotherapies. Since pravastatin produces fewer adverse drug-drug interactions than other commonly-prescribed statins, we designed a Phase 1 trial to estimate the maximally-tolerated pravastatin dose (MTD) when it is co-administered to AML patients before and during an idarubicin-plus-cytarabine induction (Ida/HDAC) regimen. We began this trial with pravastatin at conventional doses, and have already safely treated 4 patient cohorts. We have seen encouraging clinical responses, in association with dose-dependent reductions in serum cholesterol. In assays of AML cell samples from the first 3 patients, we found that 4-day, conventional dose pravastatin treatments can effectively reduce cholesterol levels in AML cells. We are now requesting funding that will allow us to complete this Phase 1 trial and to use validated, laboratory tests to analyze samples from patients treated with statin-plus-lda/HDAC and from patients treated with chemotherapy only. These studies will compare the pravastatin MTD with bioeffective pravastatin doses and thereby inform the design of clinical trials testing pravastatin's ability to improve chemotherapy outcomes in AML. Our data could have broad significance for other less experimentally tractable, statin-sensitive cancers. ? ?
| Kornblau, Steven M; Banker, Deborah E; Stirewalt, Derek et al. (2007) Blockade of adaptive defensive changes in cholesterol uptake and synthesis in AML by the addition of pravastatin to idarubicin + high-dose Ara-C: a phase 1 study. Blood 109:2999-3006 |
