New Treatment Holds Promise as a Trojan Horse Against Cancer

Mona Al-Gizawiy, PhD, had a problem. She needed her rats to eat an experimental cancer drug every day without the stress of being force-fed because the study needed to resemble the patient experience. Then she came across a study from a completely different field that had mixed drugs into the popular spread Nutella.

Gallium maltolate, the compound Dr. Al-Gizawiy had spent years investigating as a potential cancer therapy, is a powder – easy to weigh, easy to dose, and easy to mix into a small portion of the spread.

It took some training to get the rats to accept it. “They’re used to just eating rat chow,” she says. But once they did, the approach turned out to be more than just practical.

Rats that weren't feeling well didn't always finish their serving, much the same way a patient might skip a pill. Observing this, Dr. Al-Gizawiy used the leftover drug mixture in the dish as a proxy for patient compliance, giving researchers something they could accurately track and correlate with outcomes.

As with so much in Dr. Al-Gizawiy's career, it was a methodical solution to a stubborn problem. Now, as an assistant professor of biophysics at the Medical College of Wisconsin (MCW) with a $2.4 million R01 grant from the National Institutes of Health, she is applying that same ingenuity to one of medicine's most heartbreaking challenges: aggressive brain tumors in infants and young children.

"Children aren't small adults when it comes to brain tumors," she says. "The treatments are very harsh and can have adverse long-term effects. They can cause developmental cognitive delays, and radiation can cause secondary tumors down the road. We thought if we could introduce a safe drug that helps kill the tumor cell, maybe we can pull back on some of those harsher therapies."

A Pill to Swallow

When she joined MCW, Dr. Al-Gizawiy split her time between two laboratories – including that of Christopher Chitambar, emeritus professor of medicine and biophysics, Division of Hematology and Oncology, who had spent years studying gallium compounds in lymphoma and leukemia.

Dr. Chitambar had been working with older gallium formulations then received a newer compound: gallium maltolate. When he mentioned his findings to Kathleen Schmainda, PhD, a professor of biophysics whose lab studies brain tumors, the two wondered: could gallium maltolate work against glioblastoma or atypical teratoid rhabdoid tumors, two particularly devastating type of cancer?

Dr. Al-Gizawiy ran the cell culture experiments. It worked.

The next question was whether it would work in living animals. It did – but the early rat studies, while promising, left room for improvement. The drug had to be administered intravenously via implanted pumps, which was effective but would be inconvenient for human patients.

"The whole point of gallium maltolate is that it can be given orally," Dr. Al-Gizawiy says. Previous gallium compounds were salt based and had to be injected to avoid damaging the kidneys. "Patients would prefer to just have a pill to swallow. They don't want to come in, get hospitalized, sit there for hours getting a chemotherapy infusion."

Iron Impersonator

Gallium maltolate works through a form of cellular deception. Cancer cells, which grow rapidly and require enormous energy, have a far greater need for iron than normal cells. Iron enters cells via a transport protein called transferrin, which carries iron through the bloodstream and delivers it to receptors on cancer cell surfaces.

Gallium can hijack this system. Its ionic charge is similar enough to iron's that transferrin mistakes it for the real thing, escorts it to the cell, and the cell takes it in.

"It's like a Trojan horse," Dr. Al-Gizawiy says. "The cell thinks it's getting iron, but it's not. Once it's inside and reaches its destination, it shuts down the processes that depend on iron – mitochondrial respiration, energy production, DNA synthesis, DNA repair."

That last point is particularly important. One reason cancer cells survive radiation and chemotherapy is their active DNA repair mechanism. Gallium maltolate appears to disable it.

Because iron dependence is common to all rapidly dividing cancer cells and not limited to a specific mutation found in only a fraction of patients, the compound is potentially "tumor agnostic," with applications across cancer types, says Dr. Al-Gizawiy.

A Gentler Treatment

One of the most remarkable aspects of gallium maltolate, in Dr. Al-Gizawiy's observation, is what it doesn't do. Unlike conventional chemotherapy, it appears not to cause the systemic toxicity that makes so many cancer patients feel profoundly ill.

Jennifer Connelly, MD '03, GME '08, FEL '09, professor of neurology at MCW, launched a Phase 1 clinical trial in 2022 to test gallium maltolate's safety in human glioblastoma patients. The participants described not feeling like a cancer patient while taking the drug. Dr. Al-Gizawiy believes she understands why.

"Normal cells are not really affected," she says. "The tumor cells die off. We see this in the rat studies too – the rats on gallium show normal behaviors throughout the trial. Eating, drinking, grooming, playing, curiosity, interaction. They're in much better physical condition, even at the end."

The Phase 1 trial, led by Dr. Connelly with Dr. Chitambar, confirmed the drug's safety profile in adults and showed encouraging early signs of efficacy. It is in the process of being advanced to Phase 2. The early success in adult glioblastoma set the stage for the pediatric work – and for the R01 grant Dr. Al-Gizawiy received.

Pediatric Tumors and Safety Profiling

With the new grant, Dr. Al-Gizawiy has two main goals. The first is to rigorously document how gallium maltolate affects normal tissues – not just the brain, but the liver, kidneys, and other organs. This matters because clinical trials can only go so far in examining patients' internal organs.

"You can't go to patients and say, 'We're going to take pieces of your liver and double-check,'" Dr. Al-Gizawiy says. "That's the point – to build a very in-depth safety profile in animals that can fast-track clinical trials down the road."

The second goal is to understand why some tumors respond better than others. In cell cultures and animal models, Dr. Al-Gizawiy's team has seen a wide range of sensitivity to gallium maltolate. Some cell lines are killed at very low doses. Others require high doses and still show limited response.

"This iron process – this increased need for iron to survive and grow – is ubiquitous to all cancers," she says. "But we still see differences in sensitivity. We're trying to figure out what else might be at play."

To do that, she is collaborating with Shama Mirza, PhD, at the University of Wisconsin-Milwaukee, whose lab specializes in proteomics. The goal is to find molecular markers that predict which patients will respond to gallium maltolate and at what dose.

The grant also includes MRI monitoring of tumor growth, repeat biopsies during treatment, and behavioral studies of rats. It builds on a pilot study that produced a thrilling result – a rat that survived eight months, compared to the typical 30 days for untreated animals, after receiving gallium maltolate combined with reduced-dose radiation.

"We only had a couple of rats, but we had a rat survive for eight months versus 70 days for previous treatments. We were like, 'Oh yeah, it works,'" she says.

A Cancer Survivor Herself

Dr. Al-Gizawiy is also a breast cancer survivor. She is candid about how that shapes her perspective – and about her efforts to keep her scientific judgment clear of bias.

"I don't want to be biased," she says. "But I see the potential.”

She has a second grant currently under review at the National Cancer Institute that would fund animal studies of gallium maltolate in breast cancer that has spread to the brain, with a longer-term aim of launching a breast cancer patient trial.

She is also working with Abhay Chauhan, PhD, MPharm, BPharm, an associate professor in the MCW Pharmacy School, to develop alternative formulations for patients who cannot swallow pills, including infants and elderly patients.

"We have ideas galore," she says. "It's really just a matter of funding."