Over the past 25 or so years, high-throughput screening of small-molecule libraries has been a very efficient and remarkably successful way of identifying drug discovery leads. The list of FDA-approved drugs developed from “hit” compounds identified in small-molecule screens is growing longer and includes cancer therapeutics like Tarceva® (erlotinib), Iressa® (sorafenib), and Nexavar® (sorafenib).
While small-molecule screens remain a drug discovery mainstay, an emerging application of small-molecule screening is drug repurposing or repositioning. According to many experts, the number of repurposing opportunities is large and increasing rapidly.
Drug repurposing presents new avenues of discovery
Drug repurposing is the use of known drugs and compounds to treat new indications or the rescue and retooling of failed candidates to focus on different conditions. Repurposing has been utilized more and more in the last few years as pharmaceutical companies face shriveled pipelines, and also as nonprofit organizations seek to develop low-cost therapeutics in areas in which Big Pharma has no interest in investing.
According to James Cardelli, Ph.D., CEO at Segue Therapeutics, orphan or rare diseases are a natural fit for such repurposing efforts. Segue Therapeutics is an early-stage biotech company that leverages a proprietary high-content imaging platform to discover and commercialize repurposed drugs. Cardelli points out that their approach is to “Combine the faster, less risky, and cheaper model with funding from philanthropic organizations and you have a winner.”
One of the company’s first screens was to discover drugs blocking fibrosis. “For this screen, we used a high content imaging platform to screen for repurposed drugs that prevented the differentiation of myofibroblasts, a very important event in fibrosis. Very few drugs are available that prevent or reverse fibrosis. We are also developing a number of different high-content imaging screens for different pathways that are important in tumor invasion, formation of lipid-laden macrophages, and so forth,” Cardelli adds.
By all accounts, drug repurposing should reduce development costs and shorten time to market compared to traditional drug development. In addition, because the repurposed drug has already passed a significant number of safety tests, the risk of failure due to adverse effects should also be reduced.
By all accounts, drug repurposing should reduce development costs and shorten time to market compared to traditional drug development.
All of these factors have ignited the global market for drug repurposing, which is expected to grow to nearly $31.3 billion by 2020, from about $24.4 billion in 2015, with a compound annual growth rate of 5.1% for the period, according to BCC Research.
Image: Seque Therapeutics
Collaborative efforts make drug repurposing work
Before Segue moves a repurposed drug forward, it needs to pass a filter test, Cardelli says. Questions that Segue asks include: Is it off-patent? Is it FDA-approved? Is there prior art for it being used in the new indication being studied? Is it still being made?, Does it work in a relevant animal model for the disease being studied? Does it work better in combination with another repurposed drug?
Without a doubt, an efficient drug repurposing effort requires significant clinical development know-how as well as access to molecular data and appropriate analytical expertise. Novel analytical tools are increasingly at the forefront of repurposing, with bioinformaticians often relying on text-mining approaches to find connections between drugs and diseases. Not surprisingly, strategic collaborations are de rigueur in this field in order to increase the likelihood of success.
One such collaborative project is Repurposing Drugs in Oncology (ReDO), an international group that seeks to quickly find new and effective cancer treatments that have low toxicity and are cost effective. This group employs a literature-based approach using all forms of published data to find compounds to repurpose. “That means we make use of the results from published small-molecule screens, in silico approaches, individual case reports, and clinical trials,” explains Pan Pantziarka, Ph.D., of Anticancer Fund (ACF) and coordinator of ReDO. “This narrative approach allows us to synthesize and summarize data in a way that other methods cannot do.”
While there seem to be plenty of compounds ripe for repurposing, ReDO has found that relevant information on the candidates themselves is often hard to obtain, which impedes repurposing efforts. “It becomes difficult when we cannot access data from old journals, unpublished trials, and so on, The situation with unpublished trials is especially galling in that these trials may contain useful data that enable us to reject some compounds or to focus more clearly on others. Human data is the most useful source of data for repurposing, particularly in the cases where there are positive signals that have been neglected in the past,” Pantziarka says.
Several drugs are currently being studied for repurposing
Last year, ReDO published a paper in eCancer (“Repurposing Drugs in Oncology (ReDO)—Propranolol As an Anti-Cancer Agent”) describing evidence that propranolol, a beta-blocker used to treat tremors, angina, hypertension, and other heart conditions, is effective at multiple points in the metastatic cascade. Further clinical investigation of propranolol’s anticancer effects was recommended, and a number of trials are currently ongoing for angiosarcoma. “There is also good evidence that propranolol, in combination with other repurposed drugs, improves cancer outcomes following curative surgery—it appears to reduce recurrence rates. We are working with a number of clinical groups on developing trials for both these very different interventions using propranolol,” Pantziarka adds.
Other repurposing examples from the literature include a 2016 paper in eLife (“Salicylate, Diflunisal, and Their Metabolites Inhibit CBP/p300 and Exhibit Anticancer Activity”) in which salicylate acid, a widely used anti-inflammatory drug, was proposed to have even greater utility. A research team from Gladstone Institutes found that salicylate blocks protein acetylation and thus could have potential in treating certain blood cancers that rely on the p300 enzyme to grow.
"Salicylic acid is one of the oldest drugs on the planet, dating back to the Egyptians and the Greeks, but we're still discovering new things about it," said senior author Eric Verdin, M.D., associate director of the Gladstone Institute of Virology and Immunology. "Uncovering this pathway of inflammation that salicylic acid acts upon opens up a host of new clinical possibilities for these drugs."
In addition, Irish scientists from Trinity College and St. James’s Hospital reported in Onocotarget last month (“Targeting the Cancer Stem Cell Marker, Aldehyde Dehydrogenase 1, to Circumvent Cisplatin Resistance in NSCLC”) that an FDA-approved alcohol aversion drug, disulfiram (Antabuse ®), which has been used to treat alcohol addiction for over 60 years, should be investigated as a cancer therapy. According to the team, disulfiram restricts the activity of aldehyde dehydrogenase (ALDH), which has been implicated in cisplatin resistance in non-small-cell lung cancer.
"The development of novel anticancer drugs against various malignant tumors is both time-consuming and expensive and involves preclinical and clinical testing. Finding new uses for existing drugs…may allow for new uses of an old drug that may lead to the discovery of new treatments. Such repurposing is a proven shortcut between the research laboratory and the clinic," explained Lauren MacDonagh, Ph.D., first author on the Oncotarget paper.
Drug repurposing has tremendous potential to help quickly and cost-effectively find therapeutics that could help cure cancer and treat chronic diseases. However, it is not a panacea, and some of the enthusiasm about repurposing will likely abate as the nuances of successfully repositioning a drug become clearer. Rather than an alternative to traditional drug discovery, it is likely that repurposing will become a very useful complement that will help expand the repertoire of drugs available to improve human health.