Blocking DNA Repair to Fight Cancer

Aggressive tumors are hard to treat because their DNA is constantly repairing itself. Yet Yale researchers may have found a way to change that.

A picture of a DNA ladder.

DNA is surprisingly good at repairing itself–especially in aggressive, fast-growing tumors. So, to truly defeat cancer cells, scientists must find ways to go beyond just injuring them to actually disarm them.

When a person is given a diagnosis of cancer, one question rises above the rest: Can it be cured?

That answer is not always clear. Traditional treatments such as chemotherapy and radiation therapy work by damaging the genetic material that makes up cancer cells. Theoretically, that should kill them. In a perfect world, it would be a cure.

But it does not always work. The problem is that DNA is surprisingly good at repairing itself, especially in aggressive, fast-growing tumors. To truly defeat cancer, scientists must find ways to disarm cancer cells, not just injure them.

That is the idea behind cutting-edge research under way at Yale Medicine. By targeting the repair mechanisms that allow cancer cells to keep coming back, doctors hope to create the next generation of treatments.

The roots of this research go back to the 1970s and 1980s. Here at the Yale School of Medicine, Dr. Aziz Sancar (now at the University of North Carolina), started the research that ultimately led to his being one of three recipients of the 2015 Nobel Prize in chemistry. Even before that, others at Yale were pioneering the field.

Now, years later, Yale Medicine doctors continue to build on that rich history of inquiry into DNA repair to change the way they fight chronic diseases such as cancer.

“We’ve had a number of faculty continue that tradition,” says Peter Glazer, MD, PhD, chair of Yale Medicine’s Department of Therapeutic Radiology. “And there are a lot of exciting things still happening today.”

One of the best examples is the work of Ranjit Bindra, MD, PhD, assistant professor of therapeutic radiology and pathology. Dr. Bindra, who specializes in brain tumors, spends about half his time at Yale Medicine treating patients. The other half he spends in his lab, working to develop new ways to destroy cancer. 

Understanding DNA repair

To understand the research happening at Yale Medicine today, it helps to know where it started. Not long after the discovery of DNA’s double helix in 1952, scientists around the world began to wonder about the processes by which those genetic materials became damaged—for example, from radiation, viruses or old age.

They were also curious about how, in many cases, damaged DNA seemed to repair itself. This must be what regularly happens, they reasoned. Otherwise no multi-celled organisms on earth would be able to exist, at least not for long.

Much of this work was done by Yale researchers Paul Howard-Flanders and Richard Setlow in the 1950s and 1960s. In fact, many consider the pair to be the true discoverers of DNA repair.

The inquiries they started continued at Yale for several decades, with one of Howard-Flanders’ postdoctoral students, Dean Rupp, and then with Rupp’s postdoctoral student Dr. Sancar. (Rupp, PhD, is a professor of therapeutic radiology.)

In 1983, Dr. Sancar and Rupp published a paper describing how bacteria can repair damage to its DNA caused by ultraviolet radiation. Years later this would become one of the studies cited in the Swedish Royal Academy’s decision to award Dr. Sancar the Nobel Prize.

Healthy cells are not the only ones that repair themselves. DNA repair has become a hot topic in cancer research because cancer cells, which multiply much more quickly than normal ones, also suffer DNA damage.

“Cancer is a disease of uncontrolled proliferation,” Dr. Bindra says. “Its cells acquire so many mutations that they don’t know right from wrong, and they begin replicating exponentially.”

Replication at such a fast pace allows tumors to grow at alarming rates, he says, but it also causes inherent damage to the cells’ genetic structure.

Too much damage prevents cells from functioning, so cancer cells have to repair themselves regularly. When DNA strands are severed, special proteins swarm the area, mending the breaks. Those repair mechanisms also spring into action when cancer DNA is damaged during radiation therapy or chemotherapy. That is why the disease often comes back after treatment.

For Dr. Bindra, cancer cells’ ability to repeatedly fix themselves is a double-edged sword.

“On one hand, it allows the cells to continue to grow and mutate,” he says. “In that sense, DNA repair is central to genomic instability and cancer progression. But on the other hand, it’s also a very important target—an Achilles’ heel—for targeting these cancer cells selectively.”

That is where his research comes in. Because cancer cells grow so fast, he says, they are more easily identifiable in the body. In a way, that makes them more vulnerable.

In his molecular biology lab, Dr. Bindra and his colleagues investigate drugs that could potentially be combined with radiation therapy and chemotherapy to fight cancer more effectively than current treatments alone. They do this by targeting specific genes and mutations related to DNA repair that are found in cancer cells.

‘Dramatic responses’

One drug that has shown promise in Dr. Bindra’s lab is mibefradil, a medicine used in the 1990s to treat high blood pressure.

After sifting through tens of thousands of small molecules, a process called high-throughput drug screening, Dr. Bindra’s team discovered that mibefradil could inhibit DNA repair in brain tumor cells. This would make radiation therapy more effective at killing them without causing extra harm to surrounding healthy tissue.

Dr. Bindra is currently testing his hypothesis in a clinical trial at Yale Medicine. He is working with patients who have recurrent glioblastomas. Glioblastoma is an aggressive type of brain cancer that usually returns even after conventional treatments.

Study participants are given mibefradil along with radiation therapy. Tissue samples from their tumors are brought back into the lab for analysis.

The results look optimistic. While people with recurrent glioblastoma typically have an average survival rate of only about six months, Dr. Bindra says, his trial participants have survived, on average, about a year so far. Although those results are preliminary, Dr. Glazer says they are promising.

“It’s impacting patients as we speak—patients who don’t have a lot of options,” he says. “There have been some very dramatic responses, so there’s a lot of excitement about what Ranjit’s been able to do.”

From bench to bedside

Dr. Bindra will soon lead a larger study. The trial will be expanded to offer the treatment to newly diagnosed glioblastoma patients at several hospitals across the country.

That is not all. Says Dr. Bindra: “We’ve identified several other FDA-approved drugs that appear to have activity in brain tumors, as well.” He said he hopes to apply that same paradigm to those medicines and determine whether they might also be useful in a therapeutic setting.

That he is focusing on existing medications approved for other conditions is important. If shown to be successful in treating cancer, these drugs can make it to the market much faster than a new molecular entity, which could take years to pass the drug application process.

Dr. Bindra’s studies are only a small part of the life-changing science at Yale Medicine.

“Our department takes pride in having a deep understanding and respect of the pathways involved in DNA repair, but also in knowing that we’ve probably just scratched the surface,” Dr. Bindra says. “You can walk up to almost any faculty member here and learn about something they’re doing related to DNA repair that is very novel, out-of-the-box and backed by good, rigorous scientific inquiry.”

Every day the Therapeutic Radiology Department builds on research started at Yale Medicine many years ago, bringing hope for cancer cures that once seemed out of reach.

“Our main goals are to bring findings from the lab bench directly into the clinic, and we have infrastructure at Yale that allows us to do just that,” Dr. Bindra says.