Spurred into Action: Discovering the Origins of Rhabdomyosarcoma

Taking the reins

Meanwhile, in a lab in the Danny Thomas Research Center at St. Jude, oncologist and researcher Mark Hatley, MD, PhD, was having a “eureka” moment.

When it comes to the origins of rhabdomyosarcoma, he discovered, appearances can be deceiving.

For decades, scientists worldwide had assumed rhabdomyosarcoma developed from immature muscle cells. But Hatley and his fellow researchers at St. Jude proved the cancer can originate in the inner surface of blood vessels tucked into the spaces between muscle fibers. Identifying the cell where rhabdomyosarcoma begins may help scientists improve the diagnosis and develop new treatment approaches for the disease.

“Under the microscope, rhabdomyosarcoma looks like muscle cells,” Hatley explains. “But just because someone lives in Memphis doesn’t mean they’re from Memphis. Similarly, just because rhabdomyosarcoma looks like muscle cells doesn’t mean it arises from muscle cells.”

Although this type of cancer often occurs in the muscles, it also can develop in tissues that lack skeletal muscle, such as the bladder, prostate, salivary gland, abdominal fat and liver. Until now, no one had been able to fathom why that happened.

 “Rhabdomyosarcoma occurs all over the body, and the location of the tumor is pivotal to how patients survive,” Hatley says. “The tumors that arise around the eye are much different than tumors that arise in the arm, and clinically they behave completely different and their survival is much different.”

Unbridled enthusiasm

Brieanna and her family say they were drawn to St. Jude because of its world-class reputation for both research and clinical care.

“We had to find the best place for her to receive treatment,” explains her mom, Amanda.

Brieanna enrolled in a clinical trial that combines chemotherapy, surgery and proton beam radiation. St. Jude has the world’s first proton therapy center designed solely for children. The hospital is also home to a cadre of dedicated experts such as Hatley.

As a physician-scientist, Hatley spends most of his time in the lab working to better understand the biology of cancer. But he also cares for children in the hospital, which allows him to hone his clinical skills while sharing knowledge gleaned from his research.

“By spending most of my time in the lab, I can really focus and ultimately help more kids,” he explains.

Hatley says he marvels that one institution can house many of the world’s top experts in science and medicine.

 “The depth and breadth of the researchers here is absolutely amazing,” he says. “These scientists are independently giants in their field.”

St. Jude is also home to such distinguished clinicians as Alberto Pappo, MD.

“He literally wrote the book on sarcomas,” Hatley says. “He’s one of the main reasons I came to St. Jude. It was the coupling of all this amazing science, these resources, and the ability to work with the leading sarcoma doctor in the world.”

Changing horses midstream

The trail to discovering the origins of rhabdomyosarcoma has been long and circuitous. Years ago, Hatley approached the problem by activating certain proteins known to play a role in the disease. He then deleted tumor suppressor genes at various stages of muscle development. But the tumors that formed were not the ones he sought.

“We would never get the cancers we were looking for,” he says.

Then a researcher at another institution made an unexpected discovery while investigating cellular machinery called the hedgehog pathway. Activating the pathway caused tumors to form. Hatley and his colleagues realized that the tumors were rhabdomyosarcoma.

 He has spent the past six years trying to figure out which cells were giving rise to those tumors.

“We knew it wasn’t muscle,” he says, “but I always thought it was a type of metabolic fat called brown fat.”

He ultimately proved his hypothesis wrong. But in the process, he discovered the answer that had eluded scientists for decades: Rhabdomyosarcoma begins in cells that would normally develop into the cells that line the inside of blood vessels.

“That could explain why these tumors occur in places that aren’t skeletal muscles,” Hatley says. “Every part of the body has blood vessels.”

Galloping ahead

In addition to learning the cell of origin for rhabdomyosarcoma, the research team found evidence that the disease process begins before birth. They also suspect that tumors occurring in different parts of the body have diverse sources.

 By understanding the origins of rhabdomyosarcoma, Hatley hopes to uncover new ways to eradicate the disease.

“We’re still using the same therapy that was used over 40 years ago,” he says. “In leukemia, we’ve made landmark changes, pushing survival from 4% to 94%. But for rhabdomyosarcoma, we’re still sitting at about 70% survival. And for kids who have the highest-risk disease, the survival is around 20%. We need to do better.”

Now that researchers have figured out where rhabdomyosarcoma comes from they’re trying to figure out how it happens.

 “A pie-in-the-sky idea would be if we could determine how those early transformations occur, we could give them a drug to inhibit that process in patients with a predisposition to rhabdomyosarcoma,” Hatley says. “If we could win the scientific lottery, that’s what we’d want.”

Chomping at the bit

During the past couple of years, Brieanna has completed many chemotherapy treatments, followed by surgery and six weeks of proton therapy. Her mom says the care has been exemplary.

“It was surprising to me to realize that the main concern at St. Jude is to do what’s best for her—regardless of what the insurance is going to approve,” Amanda Elmer says. “To me, that’s huge.”

As she finishes her maintenance chemotherapy, Brieanna spends much of her time reading books and dreaming about horseback riding.

An avid reader since age 3, she attained a high school or higher reading level when she was in the third grade. She enjoys books about animals, especially horses. She also likes to reminisce about her favorite horse, Apollo.

“He’s a chestnut roan,” she explains. “He’s brown with bitty, bitty little speckles that are like blue roan colors. He’s really pretty. I miss him a lot.”

Thanks to St. Jude, Brieanna is convinced she’ll be back in the saddle again soon.

From Promise, Summer 2018