A new way to counter ovarian cancer’s drug resistance

Author:

Karen Cowen Dahl
Karen Cowen Dahl

At the Harper Cancer Research Institute, Karen Cowden Dahl is leading research on ARID3B, a mysterious gene that could hold promise for detecting and treating types of ovarian cancer.

Standing at a microscope in her Harper Hall laboratory, Karen Cowden Dahl, adjunct assistant professor of chemistry and biochemistry at the University of Notre Dame and assistant professor of biochemistry and molecular biology at the Indiana University School of Medicine-South Bend, is scanning through a petri dish filled with cancer cells that could represent a major step forward in ovarian cancer research.

Cowden Dahl has found a gene that could be a key to understanding ovarian cancer. That gene is ARID3B, a ubiquitous but poorly-understood transcription factor. All over the body, ARID3B acts like a switchboard operator, turning genes on and off to help cells divide and grow properly. ARID3B is an essential component for growth—embryos can’t survive without it—but in cases of ovarian cancer, ARID3B appears far more frequently than normal. Somehow, ARID3B gets its wires crossed.

Ovarian cancer is especially cruel because it is so hard to detect and hard to fight. While other types of cancer like breast cancer have reliable indicators that allow for early detection, ovarian cancer is hard to catch in its early stages.

“Ovarian cancer is one of the leading causes of cancer death in women,” says Cowden Dahl. “It’s very aggressive, and 75 percent of women who have ovarian cancer have advanced disease because it’s so hard to detect and the symptoms are very vague.”

As a result, almost all ovarian cancer patients receive the same treatment: surgery and a cocktail of carboplatin and taxol, two chemotherapy drugs with debilitating side effects like nerve damage, kidney damage, hair loss, and immune system breakdown. The treatment is an imprecise, scorched-earth approach, but it represents the best available option—and that’s the problem, says Cowden Dahl.

“Most people respond very well to treatment, but most will relapse,” she says. “Once they relapse, they never survive. [Their cancer becomes] resistant to the therapy. To me, that’s a major problem. We’re not well-suited to treat people with these treatments. We can stop [the cancer] for a while, but if it learns, there’s no stopping it.”

So Cowden Dahl’s efforts to understand ARID3B are promising for two reasons. First, “we can use ARID3B as a marker,” she says. “We’ve shown it’s higher in ovarian cancer than it is in the normal ovary—suggesting that if there’s more of it, it might be doing something to promote cancer.”

Second, ARID3B may help researchers find a way to destroy tumors before becoming drug-resistant. The potential target? Cancer stem cell genes, which trigger the production of cancer stem cells that help tumors adapt to chemotherapy. Eliminate the cancer stem cells, and the drug resistance might disappear.

“Cancer stem cell genes are highly expressed when ARID3B is introduced into cancer cells,” Cowden Dahl says. “If we could target some of those genes, we might be able to come in with a therapy… and kill that tumor.”

Sharon Stack, the director of the Harper Cancer Research Institute, says Cowden Dahl’s research has great potential. “Karen has some very compelling results suggesting a role for ARID3B not only in ovarian cancer progression, but in chemoresistance as well” says Stack, a professor of chemistry and biochemistry at Notre Dame. “These data suggest that ARID3B could perhaps be developed into a biomarker to predict—in advance of highly toxic chemotherapy treatments—which patients are likely to respond versus those that will eventually relapse. This could provide women with ovarian cancer, and their physicians, with important information that may influence treatment decisions.”

Cowden Dahl starts her research process by injecting human cancer cells, engineered to make varying amounts of ARID3B, into mice. Magnified on the microscope’s monitor, most of the cancer cells are roundish with a tightly-defined nucleus, like eggs cooked sunny side up. But about 10 percent of the cells are deformed, as if the eggs had been splattered against a wall. These are mesenchymal cells. Cowden Dahl has nicknamed them “spider cells” or “scorpion cells” because of their bizarrely splayed tendrils, a deformation resulting from the cells’ extreme reaction to excess amounts of expressed ARID3B. Because of the dramatic shape-shifting, she says, mesenchymal cells lose their ability to behave like normal ovarian cells, which normally clump together like cobblestones.

“If you lose that ability, it makes it easier for the cells to wander around,” says Cowden Dahl. “They’re very migratory. They’re very invasive.”

It’s not exactly clear how ARID3B causes the deformation. ARID3B “does have some effect on cell shape and the cells’ ability to stick to things,” Cowden Dahl says, “but we haven’t figured out why that is yet.”

It’s a familiar theme in cancer research: Each correctly placed puzzle piece seems to open up even more gaps in the puzzle. Cowden Dah’s lab team recently completed an experiment comparing two forms of ARID3B: short form and long form. Cowden Dahl had predicted that the short form would cause cancer in mice, while the long form caused cell death. To her surprise, the exact opposite occurred: Long-form ARID3B triggered both big tumors and cell death, while the short-form version seemed ineffective.

“We think it comes down to the concentration issue,” she says, undaunted. “If you have a lot of ARID3B in there, it causes cell death. But if you have a medium amount, it causes tumor growth.”

Besides these vitally important research questions, Cowden Dahl is driven by a personal motivation.

“Cancer’s always been a big part of my life,” she says. “My mother died of cancer when I was seven. And three of my grandparents died of cancer. So that’s definitely an important motivator for me.”

And although the progress has been slow, it represents a giant leap. Her research has attracted significant attention from major research institutes. She has received the Howard Temin Pathway to Independence Award from the National Institutes of Health, as well as research grants from the Ovarian Cancer Research Fund, the Eck Institute for Global Health, and the Harper Cancer Research Institute.

“When I started working on this, there were really only four publications on this gene,” Cowden Dahl says. “No one really looked at what it was doing. And so we’re on the forefront of figuring out what this molecule is really doing and how it’s contributing to cancer.”

With a support team of two undergraduates, a rotation Ph.D. student and two postdoctoral fellows, plus a state-of-the-art lab for experiments, Cowden Dahl is at the frontier of ovarian cancer research. Even if it feels laborious at times.

“To me, what makes biology so interesting—and so hard—is that we don’t know.”

 

Originally published by Angela Cavalieri at harpercancer.nd.edu on February 03, 2014.