Old Drugs, New Tricks

by Sver Aune
Illustration by Emma Vought and Brennan Wesley

The time and expense of failed drug trials have been strong incentives for researchers to give older pharmaceuticals a second look. Many existing drugs—already proven safe in patients—could be rapidly repurposed for other diseases.

Raymond N. DuBois, M.D., Ph.D., Dean of the College of Medicine 
at the Medical University of South Carolina (MUSC), likens the overall strategy of drug re-evaluation to kintsugi, the ancient Japanese art of restoration. Meaning “to repair with gold,” kintsugi can describe clinical research at MUSC, where the hidden potential of old drugs is being unlocked in new ways to fill unmet patient needs. Dr. DuBois is also guiding a national collaboration to do the same with new drugs.

Dr. DuBois has illuminated aspirin’s potential to prevent colorectal cancer. A developmental biologist at MUSC is showing how cardiac glycosides—traditionally used as a therapy for heart failure—could treat a sizable portion of people with hypercholesterolemia who do not respond to statins. Scientists at MUSC are guiding an old drug for sleeping sickness toward a clinical trial for patients with acute kidney injury.

Aspirin, one of the most widely available non-steroidal anti-inflammatory drugs (NSAIDs) on the planet, has been used for decades to treat pain and fever. Within the past 40 years, research on aspirin’s molecular traits has shown how its particular anti-inflammatory properties can be used to prevent colorectal cancer.¹

For several decades, NSAIDs, which inhibit cyclooxygenase (COX) enzymes, have been known to reduce the risk of colorectal cancer. In 1994, DuBois was part of the research group that first reported how NSAIDs actually work to prevent colorectal cancer.² DuBois and his team members showed that the same enzymes were increased in colorectal cancer and drove its growth and resistance to treatment. They reported that NSAIDs, and aspirin in particular, worked to prevent colorectal cancer by inhibiting COX enzymes. Since then, several large clinical trials and additional research by DuBois and others have affirmed their original results.

Work to deduce the potential hidden in this old drug has paid off. The United States Preventive Services Task force now recommends that adults aged 50-59 should take daily low-dose aspirin (81 mg) to reduce the risk of colorectal cancer, along with cardiovascular disease.³ Thanks to aspirin, oncologists now have a better understanding of how inflammation drives growth in many other cancers as well.

Using stem cells taken from skin, Stephen A. Duncan, D. Phil., SmartStateTM Chair of Regenerative Medicine at MUSC, has found that cardiac glycosides, historically used to treat heart failure, might be repurposed in smaller doses to lower cholesterol.⁴ The discovery was made by studying a rare disease, hypercholesterolemia (FH).

Pharmaceutical company resources are often not available to develop drugs for rare diseases, such as FH; when a rare disease drug does emerge, it is often very expensive. Academic medicine researchers can fill the gap left by the pharmaceutical industry, according to Duncan. “We’re developing platforms for a whole bunch of different diseases that manifest in the liver,” said Duncan. “We felt we should start by focusing on rare diseases.”

Untreated patients with FH, who do not respond to statins, often die in their teens and twenties from cardiovascular disease due to exceedingly high levels of cholesterol. Although FH treatments have been approved, they eventually cause fatty liver disease and cost hundreds of thousands of dollars per dose.⁵

FH, though rare, has been around at least as long as the Mona Lisa, according to Duncan. In fact, Leonardo da Vinci, a master scientist, included the xanthomas characteristic of the disease on the left eyelid and right hand of the subject of his famous painting.⁶

Liver disorders are very difficult to model for drug discovery, however, because hepatocytes rapidly lose their liver-like characteristics when grown in culture. Duncan had two research goals: to generate a stable source of hepatocytes and to reliably model hypercholesterolemia in those cells when grown in the culture dish.

Drawing upon his expertise in stem cell engineering, he pushed skin cells, obtained from a patient with FH, to transform into pluripotent stem cells and then liver-like cells. This provided him the steady supply of hepatocytes he needed. Since the cells were from a patient with FH, the liver cells maintained their hypercholesterolemia phenotype in culture.⁷

Duncan’s research group treated their FH liver cells with a drug library of over 2,000 small molecules that includes nearly every drug that has been or is currently being used in treating human disease. If one of those drugs, already tested for safety and efficacy in humans, were a “hit” in a cell culture screen, that drug could receive a new indication for treating high cholesterol in FH patients.

The results were surprising: it was a set of old drugs, cardiac glycosides, which were most effective at correcting high levels of low-density lipoprotein (LDL) cholesterol in FH hepatocytes. In fact, every cardiac glycoside tested lowered LDL cholesterol not only in those cells but also in mice with humanized livers. Remarkably, most of the glycosides lowered LDL cholesterol when applied in concentrations well below those prescribed for heart failure—the lower the dose, the lower the risk of toxicity.

The group then conducted a retrospective analysis of nearly 600 patients, which revealed similar reductions in cholesterol in patients treated with glycosides as in those treated with statins. A 200-year-old treatment for heart failure might therefore have cholesterol-lowering properties in all hypercholesterolemia patients, not just those with FH.

Duncan is currently working with Don C. Rockey, M.D., Chair of the Department of Medicine, to design clinical trials. Since cardiac glycosides have been approved in patients with heart failure, clinical trials could skip phase 1, saving time and money to provide a non-statin option for patients with hypercholesterolemia.

Another MUSC group has made a serendipitous discovery that the African Sleeping Sickness drug suramin works in the kidney in a way that is opposite to what is seen in most other cells. Rather than risking kidney toxicity, suramin might actually protect kidneys from injury.

Acute kidney injury (AKI) occurs in thousands of patients each year as a complication of drug overdose, surgery, or heart attack. As a result of AKI, kidney epithelial cells suffer damage and contribute to renal deterioration. Researchers in MUSC’s Department of Drug Discovery are examining suramin as a possible new treatment for AKI, for which no treatment is currently available.⁸ Had it not been for a fortuitous finding, the drug’s hidden potential for treating AKI could easily have been missed.

The research group, led by Rick G. Schnellmann, Ph.D., then chair of the Department of Drug Discovery and Biomedical Sciences at MUSC and currently dean of the College of Pharmacy at the University of Arizona, was using suramin experimentally in the cell culture dish to block growth factor receptors and prevent cell proliferation. Although the drug is commonly used in this manner in other cell types, the group was having trouble getting it to work in kidney epithelial cells. In fact, suramin was working perfectly, but in the exact opposite way they expected. Instead of blocking proliferation, suramin was causing kidney epithelial cells to proliferate at even higher rates. Suramin might actually help kidneys regenerate after injury.

In new experiments, the laboratory has shown that suramin helps the kidney compensate by stimulating repair and inducing regeneration of damaged cells.9 The drug even helps kidneys recover faster when given 24 hours after AKI is induced, at a time when kidney dysfunction is maximal. Since this century-old drug is already safe and effective in humans with sleeping sickness, advancing it toward clinical trials for AKI will be easier. The team is planning for a multi-site clinical trial to begin at MUSC and several other locations by the end of 2016.

“A previously approved drug that’s already been in humans that can be repurposed for a disease is a big win for patients as well as the health care system,” said Schnellmann. “Since there are no drugs to treat AKI, this will be a great opportunity to fill an unmet need.”

The future of medicine relies not just on developing new treatments, but also in understanding how the treatments we already have might be repurposed—repaired with gold—to meet patients’ needs.

¹ Wang D, DuBois RN. Annu Rev Med. 2013;64:131-144.

² Eberhart CE, et al. Gastroenterology 1994;107(4):1183-1188.

³ Bibbins-Domingo K, U.S. Preventive Services Task Force. Ann Intern Med. 2016;164(12):836-845.

⁴ Smith TW. N Engl J Med 1988;318:358-365.

⁵ Rader DJ, et al. J Clin Invest 2003;111(12):1795-1803.

⁶ Ose L. Curr Cardiol Rev 2008;4(1):60-62.

⁷ Cayo MA, et al. Hepatology 2012;56:2163-2171.

⁸ Chawla LS, et al. Nat Rev Nephrol 2011;8:68-70.

⁹ Dupre TV, et al. Am J Physiol Renal Physiol 2016;310(3):F248-F258