The poor design of clinical trials of statins in oncology may explain their failure – Lessons for drug repurposing

Abstract

Statins are widely used to treat hypercholesterolaemia. However, by inhibiting the production of mevalonate, they also reduce the production of several isoprenoids that are necessary for the function of small GTPase oncogenes such as Ras. As such, statins offer an attractive way to inhibit an "undruggable" target, suggesting that they may be usefully repurposed to treat cancer. However, despite numerous studies, there is still no consensus whether statins are useful in the oncology arena. Numerous preclinical studies have provided evidence justifying the evaluation of statins in cancer patients. Some retrospective studies of patients taking statins to control cholesterol have identified a reduced risk of cancer mortality. However, prospective clinical studies have mostly not been successful. We believe that this has occurred because many of the prospective clinical trials have been poorly designed. Many of these trials have failed to take into account some or all of the factors identified in preclinical studies that are likely to be necessary for statins to be efficacious. We suggest an improved trial design which takes these factors into account. Importantly, we suggest that the design of clinical trials of drugs which are being considered for repurposing should not assume it is appropriate to use them in the same way as they are used in their original indication. Rather, such trials deserve to be informed by preclinical studies that are comparable to those for any novel drug.

Statin as anti-cancer therapy in autochthonous T-lymphomas expressing stabilized gain-of-function mutant p53 proteins

“…To enhance the efficacy of statin treatment on xenografts, we repeated the experiment using MDA-MB-231 xenografts and placed mice on an isoprenoid-free diet (Ensure R ) 26 , administered higher and more frequent doses of a more potent statin (Pitavastatin) 26 and added Zoledronic Acid as a second mevalonate pathway inhibitor 25 ( Fig. 2d).…”

“…Zoledronic acid has been shown to phenocopy the effects of statins on mutant p53 in vitro, and reduce xenograft growth and significantly decrease mutp53 accumulation in these tumors in vivo 25 . In addition, we followed steps suggested by Abdullah et al 26 in which they explore variables that might influence anticancer statin studies to explain the inconclusive results between these studies. These authors reported that standard mouse chow suppresses their anticancer effect 26 .…”

“…In addition, we followed steps suggested by Abdullah et al 26 in which they explore variables that might influence anticancer statin studies to explain the inconclusive results between these studies. These authors reported that standard mouse chow suppresses their anticancer effect 26 . One of the putative anti-cancer statin effects is the decreased production of isoprenoids which are essential for the posttranslational modification of small GTPase oncogenes (e.g.…”

“…One of the putative anti-cancer statin effects is the decreased production of isoprenoids which are essential for the posttranslational modification of small GTPase oncogenes (e.g. Ras, Rac, and Rho) 26 . Literature data suggests the presence of exogenous isoprenoids such as geranylgeraniol present in standard mouse chow, thereby interfering with the statin effect 26 .…”

“…Ras, Rac, and Rho) 26 . Literature data suggests the presence of exogenous isoprenoids such as geranylgeraniol present in standard mouse chow, thereby interfering with the statin effect 26 . Moreover, Abdullah et al 26 report that lipophilic statins have more potent anticancer effects than hydrophilic statins, and that both higher dosing and continual dosing (once every half-life) are required for statins to exert a significant antitumor effect.…”