A no-holds-barred approach to cancer
University of Minnesota researchers are breaking the mold of cancer research to dramatically improve treatment success rates.
In clinical trials of potential therapies for cancer and other diseases, it's standard procedure to give all the patients the same drug dosage or treatment, on the same schedule, for the duration of the trial.
And hope for the best.
"The current design model is to do the whole experiment, and if it fails according to the metrics, it's over," says Paolo Provenzano, a University of Minnesota biomedical engineering professor and co-director of the University's Cancer Bioengineering Initiative.
"People are often treated in a vacuum," he continues. "If a patient doesn't respond to treatment, the researchers don't change the drug dosage or timing of administration."
The fact that flexible treatment schedules aren't widely practiced is one reason only about 5 percent of new cancer therapies are ultimately successful in clinical trials, says the Cancer Bioengineering Initiative's other co-director, biomedical engineering professor David Odde.
Odde and Provenzano lead a team of researchers who take a break-the-rules approach to improving success rates in cancer treatment. Their "radical" idea: bringing mathematical and engineering principles to bear on the problem.
Research from the Cancer Bioengineering Initiative
What follows is a glimpse into the work of six Cancer Bioengineering Initiative faculty researchers. While many come from the University of Minnesota's Medical School and College of Science and Engineering, the initiative welcomes all whose skills can help push cancer patients' survival rates past that 10 percent goal.
"Sleeping Beauty": disruptive agent of discovery
More than 25 years ago, University of Minnesota biology professor Perry Hackett discovered a long-defunct fish gene belonging to a group known as "jumping genes." After being reactivated—"awoken"—by genetic engineering, a version of this ancient fish gene was dubbed "Sleeping Beauty."
Active jumping genes can insert themselves into random locations on chromosomes, including into the middle of other active genes. David Largaespada, then an assistant professor in the College of Biological Sciences, showed that it was possible to use Sleeping Beauty to randomly disable working genes in mouse or human cells.
By "knocking out" a gene with Sleeping Beauty and noting the effects, researchers can learn what the gene does. Now a professor in the Medical School's Department of Pediatrics, Largaespada uses Sleeping Beauty to find cancer-related genes.
To search for them, Largaespada's team uses specific versions of Sleeping Beauty that randomly mutate genes by inserting themselves into or near the genes. Some versions activate (up-regulate) genes, others inactivate (down-regulate) them.
"By up-regulating a gene, we can see if it's one that can drive cancer—that is, an oncogene," Largaespada says. "But if knocking out a gene causes cancer, that means it's a tumor suppressor gene."
Genes of both types have been found this way in lymphomas, as well as colorectal, liver, breast, brain tumors, and other types of cancer.
In a stunning series of recent experiments, Largaespada's group has used Sleeping Beauty in an entirely new way: to identify mouse genes linked to the potentially lifesaving ability of some T cells—vital white blood cells of the immune system—to resist exhaustion when fighting cancer cells. They found one such gene, called BACH2.
When they engineered multiple copies of BACH2 into new mouse T cells to amplify the effects of the gene, those cells exhibited the ability to resist exhaustion.
Group of various cancer cells under a microscope.
Finally, working with collaborators at the Mayo Clinic, they engineered human T cells with BACH2, plus a gene to help the T cells detect cancer cells. When placed in mice, the T cells showed a superior ability to kill human lymphoma cells.
"We sure hope that these new types of cell engineering will work better for cancer treatment, especially for solid tumors," says Largaespada, referring to cancers other than leukemia, which affects blood cells.
Bioengineering Pop Quiz
How does the gene BACH2 help cells of the immune system?
It helps them squeeze through tight spaces between cells in an organ.
Nice thought, but think again.
It helps them resist exhaustion when fighting cancer cells.
Correct!
It keeps them from overreacting to minor infections.
No, that's a gene we haven't mentioned yet. Keep reading.
![[Left to right] Tyler Simmons, Kevin Leder, Jasmine Foo, and Kamran Kaveh.](/sites/twin-cities.umn.edu/files/scientists-mathmematician-group-shot.png)
If at first you don't succeed, call a mathematician
Consider advanced pancreatic cancer. Cancer cells in search of nutrients are migrating out from the tumor, following tiny highways built from collagen fibers in a gel matrix that fills the spaces between cancerous cells. Immune cells give chase, but can't navigate as well as the tumor cells, which will continue their spread in the abdominal cavity.
To block the migrating cancer cells, "I think we'll get a therapy that combines treatments," says Provenzano.
That may mean finding one drug to target the cancer cells and another to bolster the immune cells. Then, applying their knowledge of the physics and mechanics of the gel matrix's structure, researchers could design a third drug to cause the structure to collapse.
But with three drugs to manage, they would also call in mathematics professor Jasmine Foo to model the system and suggest details such as dosages, timing, and the order in which to administer the drugs.
"The timing and intensity of dosing processes may have the most potential for benefitting from mathematics," Foo says. "Currently, it's hard to test timing because there are countless possibilities.
"But guessing is not a good option."
Foo and Odde direct the College of Science and Engineering's Therapy Modeling and Design Center, where faculty use mathematical modeling to accelerate progress toward better medical treatments. Foo sees great potential for her field, despite the mind-boggling difficulties of modeling living systems.
"I think the use of mathematics in therapy development is evolving," she says. "For example, there's a realization that we can use math a lot in preclinical testing to avoid animal testing."
How unleashing immune cells curbed cancer
In a healthy person, T cells circulate and infiltrate bodily tissues, helping to fight off infections and keep the body free of all but healthy cells.
In response to an ordinary event like a minor infection, T cells gear up to fend off bacteria and send out protein "messages" that alert other immune cells. Those cells, in turn, prepare for action and release messages to recruit more T cells.
However, the flood of messages also sparks T cells to activate a gene called CISH, which dampens the flood. This moderates the immune response and prevents over-reactions such as excessive inflammation.
But when T cells infiltrate a cancerous tumor, moderation is not a virtue. Instead, the CISH gene hinders the body's response just when the person needs it to mount an all-out defense.
This raises the question: What if the CISH gene could be turned off in T cells that infiltrate tumors?
This summer, a team including scientists Beau Webber and Branden Moriarity, both faculty in the Department of Pediatrics, and led by Emil Lou, an oncologist in the Department of Medicine, reported how they had done exactly that. The team used the CRISPR/Cas9 gene editing technology to deactivate the CISH gene in human immune cells.
The cells were taken from the tumors of 12 patients with terminal gastrointestinal cancer. After knocking out the CISH gene, the researchers infused billions of the treated cells back into the patients, where they infiltrated the tumors. In several patients, the progression of their cancer slowed, and one young woman saw her cancer disappear completely.
It's been gone for three years.
Support the Cancer Bioengineering Initiative
The Cancer Bioengineering Initiative fuels a new era of cancer research, where engineers, mathematicians, and scientists work together to push beyond traditional limits. Your gift empowers this pioneering science, accelerating breakthroughs that can transform how cancer is treated.
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