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Researchers discover molecule that could stop movement of cancer cells

Researchers at The University of Toledo have designed a first-of-its-kind gene-targeting molecule that could serve as a therapy to stop cancer growth and to help cancer patients who are resistant to current drugs.

Dr. Terry Hinds, assistant professor in the UT Department of Physiology and Pharmacology, and Lucien McBeth, a second-year medical student, received a full international patent last fall for “Sweet-P,” a new type of anti-cancer molecule.

Dr. Terry Hinds, right, is quick to credit his research team for helping to discover Sweet-P, a new type of anti-cancer molecule. Team members are, from left, Maggie Wong, Vikram Sundararaghavan, Darren Gordon, Charles Hawk, Justin Spear, Lucien McBeth, Abdul-Rizaq Ali Hamoud, Jonathan Demeter, Kari Neifer-Sadhwani and Jonnelle Edwards.

“When cancer cells are moving to other parts of the body, Sweet-P stops the migration,” Hinds said. “There’s nothing like it out there.”

Sweet-P has the potential to be a unique anti-cancer therapy, Hinds said, but more research is needed. It first needs to be used in preclinical investigations in mice before it can be tested in human patients.

Like many scientific discoveries, this one came about as Hinds and his team were studying something else — obesity.

Their work centered on GR beta, one of two proteins that originate from a gene called the glucocorticoid receptor (GR). Hinds genetically modified stem cells to have a higher level of GR beta and hypothesized based on other studies that the stem cells would change into large fat cells.

But they didn’t. They rapidly proliferated instead.

“GR beta was driving the growth phase of the cells,” Hinds said.

This discovery led Hinds and his team to ask more questions about GR beta, which is known to cause cancer cells to grow, proliferate and migrate.

Hinds’ team focused on the place on a gene where small RNAs, in this case microRNA-144, bind on the GR beta gene. Very little is known about microRNA-144 or what it specifically controls, but reports show that levels of it are significantly higher in patients with bladder cancer.

“Typically, microRNAs suppress genes. But this microRNA activates GR beta, especially during migration,” Hinds said. “We’d never seen this before.”

No one had ever created a drug to target microRNA-specific interaction with a gene. So Hinds got to work.

The end result is Sweet-P, a peptide nucleic acid molecule that resembles DNA.

Hinds tested the molecule on bladder cancer cells and found that it did indeed suppress GR beta. It latches on to the microRNA binding site of the GR beta gene and stops the microRNA from activating the protein. If the GR beta doesn’t work properly, the cancer cells don’t migrate.

Think of it as a basketball game. GR beta is the point guard, the playmaker. It sends the basketball (a signal) to other players (the cancer cells) to move and drive to the basket (other parts of the body). MicroRNA-144, then, is the coach screaming at GR beta to go faster. Sweet-P is akin to the referee giving a technical foul to silence the “coach” and slow down the game.

Because Sweet-P targets just one specific gene interaction — between the microRNA and the GR beta gene — it could significantly reduce side effects of potential treatments created with it, Hinds said.

“It’s precision medicine at its best,” he said.

Sweet-P’s ability to target GR beta could have implications for treating other cancers in which GR beta is highly expressed, including glioblastoma, an aggressive brain cancer, and prostate and lung cancers.

Sweet-P also could be a potential treatment for other diseases, like asthma, Hinds said.

Glucocorticoid hormones (GCs), the most commonly prescribed anti-inflammatory drugs, are often used to treat asthma, as well as cancer and other diseases. A high level of GR beta can cause those hormones to become ineffective, a condition known as GC resistance. Asthma patients often have high GR beta in their airways.

“When Sweet-P inhibited the GR beta, it increased the responsiveness of GCs, so Sweet-P may reverse GC-resistant diseases,” Hinds said.

If Sweet-P someday becomes an approved therapy, Hinds, who has asthma, might be able to get rid of the EpiPen on his desk.