In the Works: Toronto team aims for a drug to make tumors hyper-sensitive to radiation
Cancer treatments, such as radiation and chemotherapy, are more shotgun-scattered than precision-targeted. They damage bystanding healthy cells as they attack the tumor tissue, causing nasty side effects.
Scientists would like to focus these therapies more narrowly on the cancer cells alone, and researchers in Toronto have come up with a new strategy. With a flick of a genetic switch, they’ve made cancer cells ultra-sensitive to radiation, thus killing tumors that normally withstand the treatment.
The team at Toronto’s Princess Margaret Hospital, which published its findings Jan. 26 in the journal Science Translational Medicine, now aims to produce the same effect via a simple drug instead of genetic engineering.
To get the effect, the scientists worked with a gene that directs formation of a protein known for short as UROD (pronounced “yuro-dee”). Normally, UROD is involved in making the heme that transports oxygen around the body inside red blood cells. But when the scientists blocked the activity of UROD in mice, it slowed tumor growth.
The scientists also found that people whose cancers had naturally low UROD levels were more likely to survive — implying that the UROD-blocking strategy might very well help in humans, as well.
Senior author Dr. Fei-Fei Liu says she is particularly interested in trying the technique in head and neck cancers, her lab’s specialty. The category — which includes cancers in the lining of the mouth, throat and nasal passages but excludes other conditions such as brain cancer and skin cancer — makes up 3% to 5% of cancers in the United States, with about 40,000 people diagnosed annually. These cancers are frustrating to treat, she says, because the tumors are in or next to the structures a person needs for swallowing, talking or breathing.
If surgically removing the tumor would be disfiguring or damage parts crucial for speaking or eating, oncologists at Princess Margaret prefer to use radiation therapy, Liu says. Unfortunately, doctors have to irradiate a broad area to make sure they get all the cancer, and the side effects are unpleasant. “Imagine how sore and uncomfortable it is when you have a sore throat from a cold,” Liu says. “When we give patients radiation, it’s exponentially worse.”
And, she adds, despite doctors’ best efforts, only 50% of people with head and neck cancers survive beyond five years.
Liu and colleague Emma Ito, who earned a doctorate in Liu’s lab, set out to find a way to make the radiation work better. They worked with cancer cells, living in dishes, that are known to resist radiation. Using a genetic trick, Ito blocked the activity of thousands of genes, one by one, and looked for dishes where, upon irradiation, at least half of the cells died.
Getting rid of UROD, she found, killed the cancer.
Ito then tried the anti-UROD treatment in cancer cells that she injected into mice. Normally, mice have noticeable tumors by nine days after injection. But with UROD gone from the cells, it took 23 days for visible tumors to appear — in other words, the lack of UROD slowed the cancer. With radiation therapy added, it took 37 days for the tumors to emerge.
Ito also treated mice that already had tumors with the UROD-blocking agent plus radiation. Their tumors grew more slowly than those in mice that received radiation alone.
The results are “dramatic,” says Dr. Wendy Woodward of the M.D. Anderson Cancer Center in Houston, who was not involved with the study. “The magnitude of the effect is not something you have to squint at to appreciate.”
Liu and Ito believe the cancer-killing effect has to do with the cell’s load of highly reactive free radicals. These molecules wreak havoc in the cell, damaging DNA and other parts.
Cancer cells already have lots of free radicals and not enough of the antioxidants that keep them in check. In fact, both radiation and chemotherapy work, in part, by further boosting the levels of these reactive molecules in cancer cells so that their DNA falls apart, they can no longer reproduce and they die.
Liu and Ito suspect that silencing UROD also adds to the cell’s free radical load. Most likely, losing UROD makes this happen because when the heme production system is broken, iron builds up — and the cell uses that iron to manufacture free radicals, nudging cancer cells closer to death.
“Knocking down the UROD seems to push them over the edge more easily,” Liu says.
Although Ito and Liu were focused on head and neck cancer, the anti-UROD treatment also worked on cells from lung, cervical, prostate and breast cancers. It also seems to be effective in conjunction with chemotherapy. Plus, some cancerous cells die after anti-UROD treatment alone, Liu says.
The scientists also looked at UROD levels in tumors from 38 people who had head and neck cancers, compared with normal tissues from five people. The cancer samples had 11 times the normal amount of UROD. And the people who had the most UROD in their cancers were least likely to survive, even after radiation therapy.
Having lots of UROD in a tumor, then, is a bad sign, and Liu thinks that doctors could use this information to help predict who needs the strongest possible radiation therapy and who could probably survive with less, and thus suffer fewer side effects.
It’s an exciting idea, Woodward says, but she adds that a larger study is needed to prove it.
Since the genetic trick the team used in its mouse and cells-in-dishes work is not a mainstream therapy, Liu is now collaborating with chemists to find a drug that would have the same anti-UROD effect. She estimates it’ll take two or three years to find a candidate drug, and years more to test it.
Doctors already have some treatments that sensitize tumors to radiation but are always looking for new, better options, says Dr. Cary Presant, an oncologist at the Wilshire Oncology-US Oncology Group in Los Angeles and former president of the American Cancer Society’s California division.
“This is an exciting new target to look at,” he says.
