Drug repurposing for cancer therapy—an introduction

Definitions

While we refer throughout to “drug repurposing” there are in fact a number of competing terms with overlapping definitions. In addition to drug repurposing, other commonly used descriptive terms include “drug repositioning,” “drug rescue,” “drug reprofiling,” and “drug rediscovery” [ ]. For the purposes of this article, we adopt the following definition of drug repurposing: the application of an existing, licensed drug to a new disease for which it is not licensed or widely used as an off-label treatment. This definition, therefore, excludes the development of previously shelved compounds that have never been licensed as pharmaceuticals. Our definition does not exclude off-label use per se, rather it excludes those instances where drugs are widely used in clinical practice to treat diseases that are not included in the licensed indications for the drug [ , ]. However, the use of off-label prescribing for new uses is included within our scope of repurposing, although as we shall discuss later, it is not an ideal end point.

In the case of oncological repurposing, there is also a notable pragmatic distinction sometimes made between “soft” repurposing—the repurposing of existing oncological drugs to new cancer indications—and “hard” repurposing—the repurposing of noncancer drugs as cancer treatments [ , ]. In reality these strategies exist on a spectrum rather than being binary categories, as shown in Fig. 1.1 .

In many respects, the “soft repurposing” side of the spectrum is the standard model in oncology—drugs are licensed for an initial cancer indication and then further developed for new indications while still within the patent-protected period—for example, a drug may be licensed as a second-line therapy and then developed for first-line or a drug developed for one cancer type may then be applied to other, often unrelated, malignancies. Such development benefits both from commercial sponsorship and from the degree of familiarity that treating physicians have with the use of these drugs in an oncological setting.

This process of soft repurposing can encompass all classes of anticancer drug at all stages of clinical and commercial development. Traditional cytotoxic chemotherapy drugs, the majority of which are generic, are still being explored for clinical use in sarcomas and other hard to treat cancers in large academic-led trials such as the Euro Ewing 2012 trial [ ]. In contrast to these efforts, which are not commercially supported, newer agents that are still within the market exclusivity period, such as immune checkpoint inhibitors, are being rapidly developed for multiple new indications in commercially supported trials. For example, pembrolizumab was first approved by the FDA in 2014 for patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. By January 2020, it has FDA approvals for over 20 cancer indications including in non-small cell lung cancer, small cell lung cancer, head and neck squamous cell carcinoma, classical Hodgkin lymphoma, and more. Indeed, it may be true to say that cancer drugs used in only a single indication are rare exceptions to a general trend of soft repurposing of anticancer agents.

However, the development of noncancer drugs as new cancer therapeutics is much rarer and more problematic, particularly in the case of generic medications. The most notable examples of hard repurposing have been thalidomide and all-trans retinoic acid (tretinoin), both drugs licensed for noncancer indications and then subsequently developed and licensed as treatments for multiple myeloma and acute promyelocytic leukemia, respectively. Hard repurposing may be more difficult to achieve in practice due to a lack of commercial incentives in the case of drugs that no longer benefit from IP protection, a topic we will discuss in more detail subsequently. A less tractable issue relates to a degree of skepticism from the medical community regarding the potential utility of noncancer drugs as oncological treatments. There may indeed be a rejection bias at work when assessing the evidence from repurposing trials, demanding a higher level of evidence for efficacy than would be expected for soft repurposing [ ].