The purpose of repurposing

The goal of developing drugs that act at a single target – the long-standing focus on discovering the 'magic bullet' – as enticing and enduring as it has been, has not proven to be a uniformly successful endeavor. Most complex disorders, including those not only in oncology but also in neurology and neuropsychiatry, whether in their initial stages or in their progression, are not mediated by a single protein target. Cancer is a heterogeneous, highly adaptive and constantly evolving disease, driven in large part by the targeted therapeutic agents designed specifically to suppress the disease. The challenges of therapeutic intervention at any one of these stages is likely to necessitate a different strategy which may not only address the existing target(s) but those that emerge following mutations or the development of resistance [1, 2]. While the development of a multitargeted single drug addressing an optimal array of targets poses several challenges, informed drug combinations have the potential to hit multi-sensitive nodes belonging to a network of both static and emerging targets. The repurposing or repositioning of existing drugs that can be used to supplement or enhance therapeutic efficacy is now an active area of research that promises to greatly expand treatment options. The article by Simbulan-Rosenthal et al. [3] is an important addition to this initiative, elegantly combining a novel rapid computational proteochemometric method [4, 5] coupled to cell-based assays to show that the anthelmintic drug mebendazole should be considered in combination with trametinib as a therapeutic option for patients with NRAS Q61mut or other non-V600E BRAF mutant melanomas. Mebendazole, discovered in the 1970s, belongs to a class of drugs that bind and disrupt tubulin polymerization. However, mebendazole binds tubulin at a site that differs from other tubulin binding agents such as vinblastine or paclitaxel and, quite remarkably, interacts with a number of other cancer targets. Several of these targets have been identified using the computational methods developed by this group of investigators and include multiple kinases as well as anti-inflammatory drugs [4, 5]. The current study focused mainly on NRAS mut / BRAF WT melanoma cells which account for approximately 21% of all melanoma cases and which are particularly recalcitrant to treatment, have shorter survival times than those of patients with melanoma harboring BRAF mutations, and are not responsive to BRAF600 inhibitors such as vemurafinib and dabrafenib. These compounds can actually enhance or inhibit the growth of NRAS mut …