An old drug with new tricks

As the hunt for effective cancer therapies intensifies, some scientists are turning back to look at old drugs in a new light. The anti-malarial hydroxychloroquine is one such drug that has been “repurposed” to fight cancer. Despite its effectiveness at blocking the resupply of needed resources to cancer cells, clinical trial results have been disappointing, in part because cancer cells eventually become resistant to the drug.

A Medical University of South Carolina Hollings Cancer Center team led by Joe Delaney, Ph.D., reports in Cell Cycle that resistance to hydroxychloroquine occurs not by restoring the cancer cells’ recycling ability, as had been expected. Rather, resistance develops due to changes in the division, metabolism and export pathways of cancer cells. These findings open the door for new combination treatments, as drugs targeting these newly identified resistance mechanisms can be administered along with hydroxychloroquine to improve outcomes.

The promise of repurposed drugs

Repurposing old drugs for new treatments is not a new concept. Aspirin was originally used as a painkiller, but after the discovery of its anti-coagulant properties, it was repurposed as a blood thinner to treat heart disease. Thalidomide, the infamous anti-nausea medication, has been recently repurposed as a treatment for certain types of cancer and even leprosy. As cancer therapy moves increasingly toward specific single-protein targets, some scientists, like Delaney, are swinging back to look at preexisting drugs to find robust, multi-target effects.

“Targeting single proteins can be extremely effective to treat cancer,” said Delaney. “However, the more specific the treatment becomes, the more likely resistance is to occur.”

Imagine a hotel hallway, and behind each door is a route for cancer development. Targeting single proteins is like welding one of the doors shut. It’s impossible to get through that door, but it’s just a matter of time before cancer picks the lock on another door and gets in. That’s why these old drugs are so promising, said Delaney – their breadth of targets padlocks several doors at once, making it that much harder for a cancer cell to work around them.

“These older molecules usually work because they have many, many targets within the cell,” he said. “If we can figure out how to use them correctly, it’s harder for cancer cells to mutate all those different points that they are acting on.”

The cancer-fighting promise and limitations of hydroxychloroquine

Originally used as a treatment for malaria, hydroxychloroquine began to be explored as a cancer therapy in the mid-2000s. The drug is known to block autophagy, a process that essentially acts as a cell’s clean-up crew.

Autophagy literally means “self-eating.” It enables cancer cells to gather up old or damaged cellular machinery and send it off either to be thrown out or recycled.

“When we think of cancer, we think of uncontrolled dividing cells,” said Delaney. “Autophagy is one of those processes that really enables a cancer cell to do just that by resupplying it with resources needed for survival and division.”

Despite the drug’s promise of killing cancer cells by blocking cellular recycling, most clinical trials using the drug have been disappointing.

“What we don’t know is why so many of these clinical trials have failed,” said Delaney. “We’re trying to figure out why hydroxychloroquine works or doesn’t work in certain situations in cancer.”

A surprising finding about resistance to hydroxychloroquine

To answer these questions, researchers in the Delaney Lab embarked on a multi-omics exploration into hydroxychloroquine’s effect on ovarian and colorectal cancer cells. They treated cells with hydroxychloroquine and then used two different whole-genome screens to identify exactly what the cells were doing to evade hydroxychloroquine attacks. With these approaches, they were able to observe how cells activated or deactivated different cellular pathways in response to continued hydroxychloroquine exposure.

“By using two completely different methods, we were able to home in on the true biological players in the system,” said Delaney.

The researchers were surprised to find that cells weren’t modifying autophagy to survive – the door that was expected to be opened really wasn’t touched at all. Instead, cancer cells were surviving hydroxychloroquine by changing their metabolism, division and export pathways.

“We thought the main interaction of hydroxychloroquine with cancer was this process of autophagy, but it appears instead that processes unrelated to autophagy may be the most important for cancer cells to survive this therapy,” said Delaney.

Setting the stage for novel combination therapies

With this discovery, the Hollings team hopes to identify drugs that could be administered along with hydroxychloroquine to prevent the cancer cells from becoming resistant to this therapy.

“Our study has identified the potential mechanisms that we will need to target with a second drug to prevent resistance against hydroxychloroquine,” said Delaney.

Combining hydroxychloroquine with drugs that affect cell division, metabolism or export could increase the effectiveness of the treatment. Additionally, using hydroxychloroquine to treat patients with cancers that already have defects in one of these newly identified pathways could be a very powerful intervention. Finally, patients without these defects could be directed to potentially more effective, less resistant treatments.

“We certainly want to understand which patients would see the most benefit to get the best result from these trials,” Delaney said.

Ultimately, these results from the Delaney Lab shed light on how repurposed drugs like hydroxychloroquine can be used to fight cancer more effectively. Specifically, they show that cancer cells resist hydroxychloroquine in unexpected ways. By using such information, scientists can create more effective combination treatments against cancer.

Vaena SG, Romeo MJ, Mina-Abouda M, Funk EC, Fullbright G, Long DT, Delaney JR.
Autophagy unrelated transcriptional mechanisms of hydroxychloroquine resistance revealed by integrated multi-omics of evolved cancer cells.
Cell Cycle. 2024 Sep 19:1-21. doi: 10.1080/15384101.2024.2402191