Immediate Utility of Two Approved Agents to Target both the Metabolic Mevalonate Pathway and its Restorative Feedback loop

Menée in vivo, cette étude suggère l'intérêt du dipyrimadole, un médicament doté de propriétés anti-agrégantes plaquettaires, en combinaison avec une statine pour le traitement des patients atteints d'un myélome multiple ou d'une leucémie myéloïde aiguë récidivante

Résumé en anglais

New therapies are urgently needed for hematological malignancies especially in relapsed acute myelogenous leukemia (AML) and multiple myeloma (MM) patients. We and others have previously shown that FDA-approved statins, which are used to control hypercholesterolemia and target the mevalonate pathway (MVA), can trigger tumor-selective apoptosis. Our goal was to identify other FDA-approved drugs that synergize with statins to further enhance the anticancer activity of statins in vivo. Using a screen composed of other FDA approved drugs we identified dipyridamole, used for the prevention of cerebral ischemia, as a potentiator of statin anti-cancer activity. The statin-dipyridamole combination was synergistic and induced apoptosis in MM and AML cell lines and primary patient samples, whereas normal peripheral blood mononuclear cells (PBSCs) were not affected. This novel combination also decreased tumor growth in vivo. Statins block HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the MVA pathway. Dipyridamole blunted the feedback response which upregulates HMGCR and HMG-CoA synthase 1 (HMGCS1) following statin treatment. We further show that dipyridamole inhibited the cleavage of the transcription factor required for this feedback regulation, sterol regulatory element binding transcription factor 2 (SREBP2). Simultaneously targeting the MVA pathway and its restorative feedback loop is pre-clinically effective against hematological malignancies. This work provides strong evidence for the immediate evaluation of this novel combination of FDA approved drugs in clinical trials.