St. Baldrick’s Scholars Dr. Alex Huang and Dr. Agne Petrosiute are studying how switching off a protein could lead to new treatments and cures for kids with brain tumors. Read on for more about their unexpected discovery, its implications for immunotherapy, and why Dr. Huang compares himself to those fuzzy little bears in Star Wars.
Dr. Agne Petrosiute (left) and Dr. Alex Huang study how the immune system can be harnessed to fight pediatric brain cancer.
Dr. Alex Huang likens himself and his colleague, Dr. Agne Petrosiute, to Ewoks battling the Death Star.
“We are the Ewoks that found the controller on this planet, and all of a sudden the Death Star cannot put up the shield anymore,” he said. “And so now, Luke Skywalker can go in there and blow it up.”
It may seem like a curious explanation, but it fits.
An Unexpected Discovery
About five years ago, the St. Baldrick’s-funded researchers stumbled upon something interesting and unexpected.
They had hypothesized that removing a certain protein, called CDK5, would stop the growth of medulloblastoma tumors, the most common brain tumor found in kids. Unfortunately, the tumors kept growing, with or without the protein.
But despite their incorrect hypothesis, the scientists’ experiment yielded something fascinating.
When they removed that particular protein, the tumor became vulnerable to attack from the immune system.
“Somehow by targeting this protein, we are making a very aggressive brain tumor that’s common in pediatric cancer, now, all of a sudden, become sensitive to our normal immune system’s ability to eliminate them,” he said. “That was curious. That was something that we just didn’t expect at all.”
Essentially, Dr. Huang and Dr. Petrosiute removed the tumor’s shielding, making the scientists a bit like those fuzzy, little teddy bears that live on Endor.
And just like in the Star Wars movie, when destroying the Death Star changed the balance of power in the galaxy, Dr. Huang and Dr. Petrosiute’s research could shift the power away from brain cancer and to the kids fighting it.
Dr. Huang shows off his Star Wars memorabilia.
Taking the Brake off the Immune System
Kids with medulloblastoma don’t have many options. It’s a tough cancer to treat, both with conventional treatments and with immunotherapy.
Traditional treatment can be just as rough as having the cancer. The current narrow band of therapies — chemotherapy, radiation, and surgery — might be saving lives, Dr. Huang explained, but they are wreaking havoc on kids’ futures.
“A patient that’s surviving these therapies has devastation as far as long-term quality of life,” he said, rattling off the late effects they might experience. “Endocrine insufficiency, growth hormone insufficiency, all the other things. So, having a non-chemotherapeutic, an ‘enhancing immune responses’ angle to treat the cancer … it’s an encouraging sign.”
Though there’s been a lot of success with treating leukemia by harnessing the immune system, brain tumors are trickier. One promising immunotherapy in leukemia, called CAR T cell therapy, uses incredibly specific, unique targets to tell the immune system which cells to destroy.
The challenge is that these types of targets are few and far between in solid tumors, said Dr. Huang.
“You can think of a muscle tumor, for example. If you construct a CAR T cell against muscle tumors, chances are the same CAR T cells are going to recognize normal muscle and it’s going to destroy the normal muscle,” he said. “There’s the challenge. How do you make a tumor-specific CAR construct?”Dr. Huang and Dr. Petrosiute happened upon a unique way of addressing that challenge: they let the immune system pick what it wants to fight, instead of telling it what to do.
“What we are doing is we are just taking the brake off the immune system,” Dr. Huang said. “We are destroying the tumor’s defense shield, so that the immune system has a chance to work against it and choose whatever it deems relevant as a target to go after, without us trying to be smart about it.”
Ambassador Isaac fought medulloblastoma as a first grader and now shows no evidence of disease. Now a fifth grader, Isaac wrestles with late effects from his treatment.
Hope on the Horizon
Aside from being a St. Baldrick’s researcher, Dr. Huang is also contributing to an immunotherapy working group in the Moonshot Initiative. With the Moonshot putting immunotherapy front and center on the national stage, the timing of their discovery couldn’t have been better for kids who don’t have time to wait.
“I think we’re in the right place,” Dr. Huang said. “There’s so much excitement with immunotherapy that there’s going to be substantial investment from both companies and the government.”
And there could be a big pay-off not just for kids with medulloblastoma, but other tough-to-treat pediatric tumors, like brainstem gliomas and ATRT, which has no known cure.
“If it goes beyond that to extend to sarcomas … or other diseases that affect pediatrics, then it’s just more hope on the horizon for kids with cancer,” he said.
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