Repurposed drugs may lend a new hand as add-ons to existing cancer treatments

Abstract

Despite the inroads made in improving treatments for a wide range of cancers, researchers are coming to grips with the unsettling realization that malignant cells still have a surprising number of escape routes. Block one, and another seems to open up.

Several recent studies, though, have suggested that chemotherapies could be made more effective if combined with drugs initially used for other purposes, such as fighting depression, reducing inflammation, or treating heart failure or pulmonary fibrosis. As add-ons to primary therapeutics, these repurposed drugs may have unexpected additive or synergistic effects that help to block more of the escape routes. As a bonus, many already have been through the lengthy and costly regulatory approval process. This advantage could help researchers to avoid the high costs and long timelines that have slowed the development of novel cancer drugs.

“Combinatory treatments that target the multifaceted oncogenic signaling network hold immense promise,” asserts a recent review of the strategy.1 “Repurposed drugs offer a potential solution to this challenge, harnessing known compounds for new indications.”

In some cases, understanding the environmental niches of cancer cells can help to inform the strategy. One recent study found that adding a drug used to treat idiopathic pulmonary fibrosis to standard chemotherapy increased survival for patients with early-stage HER2-negative breast cancer.² The antifibrotic drug nintedanib seems to work by reducing high levels of fibrosis in the tumor microenvironment. As the study authors noted, “tumor progression has been linked to stiffening of the extracellular matrix caused by fibrosis.” Loosening that extracellular matrix then boosts the effectiveness of the targeted chemotherapy.

Berend Snijder, PhD, a professor at the Botnar Institute of Immune Engineering in Basel, Switzerland, led another study suggesting that an inexpensive antidepressant called vortioxetine can shrink glioblastoma tumors, particularly in combination with existing chemotherapies.³ Dr Snijder is an expert in conducting large-scale genetic screens and adapted a high-throughput screening technology to assess how human blood and tissue, including blood cancer samples, would respond to various drugs. With its ability to characterize therapeutic responses at the resolution of a single cell, the technology identified actionable therapies for individual patients, he says.

Based on his initial success, Dr Snijder began asking whether the high-throughput screen might work for solid tumors as well. Several clinical collaborators suggested that he should try it on glioblastoma, which is badly in need of new therapeutic options. “Glioblastoma is not just a terrible disease for patients, but it’s also like a graveyard of failed clinical trials,” he says.

Dr Snijder and his team screened a variety of drugs known to cross the blood–brain barrier—an essential though insufficient property for any drug targeting a brain cancer. Starting with a complex mix of cancer and neural cells removed from patients during glioblastoma surgeries, he and his colleagues used a machine learning process to classify each cell as cancerous or healthy. Within each testing well, they assessed the cells’ response to a different drug or drug combination. “An exciting response is when we see that a drug kills the cancer cells faster than it kills the healthy cells in the same well,” he says. “So, it’s really this internal competition between trying to keep the healthy cells alive and killing the cancer cells.”

A subset of neuroactive drugs, they found, selectively killed the cancer cells at a much higher rate than the healthy cells, with vortioxetine delivering the best results. Intriguingly, the 10 or so most effective drugs have different known modes of action; this variation suggests that a more complicated mechanism may be at play. Further modeling and analysis by Dr Snijder and his colleagues have suggested that beyond their traditional roles, the drugs somehow activate a pathway that sends a rapid influx of calcium ions into glioblastoma cells and triggers a cascade of signals that block their proliferation and ultimately kill them.

The finding is still limited to anti-tumor activity in patient-derived cells and will need to be tested in clinical trials. The results, however, suggest that vortioxetine and some other candidates could have a potent synergistic effect when they are combined with existing chemotherapies, Dr Snijder says. Although traditional glioblastoma drugs seem to have a slight preference toward more mature cancer cells, the new drug candidates seem to target more immature, stem-like subpopulations of glioblastoma cells. “It’s immediately intuitive that if you just kill one or the other, you might not do as well as when you find drugs that kill both,” he says.

For a few research efforts, serendipity has led to potential strategies involving repurposed medications. Matthew Knarr, PhD, an instructor in the Department of Obstetrics and Gynecology and the Penn Ovarian Cancer Research Center at the University of Pennsylvania in Philadelphia, was studying how nerves can infiltrate ovarian tumors when he saw something strange.

After some initial tests suggested that forskolin decreased the viability of ovarian cancer cells, Dr Knarr and his colleagues in the laboratory of Ronny Drapkin, MD, PhD, director of the Penn Ovarian Cancer Research Center, launched a more in-depth examination. Dr Knarr found that the molecule had been used to treat glaucoma and tested for its potential to treat heart failure and other conditions.⁴ A water-soluble and more clinic-friendly synthetic derivative, known as colforsin daropate, retains similar biological activity.

In the laboratory, extensive experiments showed that the synthetic drug selectively killed ovarian cancer cells and shrank tumors in mice.⁵ When it was used in combination with the commonly used drug cisplatin, the anti-cancer effects were even greater. “We showed a lot of data that they work together really well synergistically,” Dr Knarr says. Mice injected with cisplatin-resistant ovarian cancer cells, for example, eventually died despite receiving cisplatin therapy. However, mice that received both cisplatin and colforsin daropate after the cancer cell injections lived significantly longer; some mouse survivors were still living when the study ended.

According to an old report that Dr Knarr hopes to test, one possible mechanism for the synergy is an increased uptake of cisplatin in the ovarian cancer cells.⁶ The laboratory’s initial work also suggests that colforsin daropate decreases levels of the oncoprotein Myc. Among patients with ovarian cancer, a significant fraction has an amplification of Myc, which suggests that they might be a good subpopulation on which to focus first for targeted therapeutics.

Dr Knarr cautions, though, that far more research is needed to test the drug’s generalizability and safety, and it is not yet clear to what it may be binding to achieve its cytotoxic effect. “When you’re working with drugs, people like to make out the primary mechanism, but there’s usually more than one thing going on at the same time,” he notes.

Dr Snijder likewise is hoping to conduct clinical trials that rigorously test both the safety and efficacy of vortioxetine as an add-on to the standard of care for glioblastoma. That goal has taken on added urgency amid anecdotal reports that desperate patients are already self-experimenting with the depressant in the absence of better glioblastoma treatment options.

Drug repurposing to improve chemotherapy still faces a perception problem and a lack of funding, Dr Snijder says, in part “because it’s not the next shiny new thing.” He is convinced, though, that adopting a mindset of optimizing existing treatments—whether pursuing better matches with known chemotherapeutics or exploring off-label effects of other drugs—will yield tangible benefits. “We now have so many drugs available that we know are predominantly safe and approved and accessible, and we’re doing a very poor job in general, I think, in matching patients with the right treatments,” he says. “There’s a lot of room for improvement.” ■