MUSC pediatric cancer researcher awarded grant to understand medulloblastoma relapse

One of the most prestigious pediatric cancer foundations in the U.S. has awarded a grant to a Medical University of South Carolina researcher to continue her pursuit of the causes of medulloblastoma relapse.

Jezabel Rodriguez Blanco, Ph.D., who has a dual appointment at MUSC Hollings Cancer Center and the Darby Children’s Research Institute at MUSC, will receive $800,000 over four years from Alex’s Lemonade Stand Foundation for Childhood Cancer.

“It’s an honor to have one of these grants,” said Blanco.

For her, solid scientific work is always in service to the patients who need new discoveries. Her lab is dotted with photos of pediatric cancer patients, a daily reminder of the reason for her work. Unfortunately, she said, the number of pictures is growing, as is the number of children with medulloblastoma.

“That pushes us to work a little bit harder and to make sure that what we are doing is not just to publish a paper and get a grant,” she said. “It is to make a difference for those that need that difference.”

 

With this grant, Blanco will work on medulloblastoma, the most common type of malignant pediatric brain tumor and one of the major causes of cancer-related death in children.

Her previous work showed how targeting a protein called Glioma-associated oncogene homolog, or GLI, on the Sonic Hedgehog signaling pathway could shrink the medulloblastoma tumor and make it less likely to relapse. The results were exciting, and the mice implanted with tumor cells previously exposed to a GLI inhibitor were doing well. But she and her team decided to keep monitoring them, far longer than they typically would.

“It was looking good,” she said. “But some mice had a relapse – it just took way longer. When we waited enough time, we saw that the tumors were still coming back in about 50% of the animals.”

The tumors came back several weeks later. This suggests that if treatment were translated for pediatric cancer patients, these patients might similarly eventually relapse. And because children should have many decades of life ahead of them, recurrence might even come in early adulthood.

“Even if we believe the tumor is gone in the child after treatment, there is always the possibility of it returning at any point in their lives. Consequently, children and their families live with the constant fear of a potential relapse,” Blanco said.

Besides the chance of tumor relapse, treatments for children with medulloblastoma are extremely harsh. These therapies, which were developed for and tested mostly on adults, can have serious long-term side effects for growing children.

Blanco described meeting a young woman in her 20s who had survived medulloblastoma but deals with a number of long-term side effects, including serious neuroendocrine and cardiovascular complications, in addition to increased chances of developing secondary cancers, because of the treatments she was given.

“She's alive. But she will deal with the consequences of the treatment for the rest of her life,” said Blanco, who is working both to prevent relapse and to target the cancer more effectively so that patients have fewer side effects.

 

Childhood cancers are different than adult cancers, she pointed out. Adult cancers are usually the results of mutations that have built up over time. But most childhood cancers come when genes that are responsible for rapid cell multiplication during embryonic development aren’t switched off at the right time.

“In the case of a kid, it’s normally just one mutation – normally an oncogene that was involved in development and for some reason at the end of the development, when it was supposed to be switched off, it didn’t. It kept on being active,” Blanco said.

“When we analyzed those tumors, we saw an enrichment in cells that resemble healthy brain components. These cells should not be in residual tumors, and we wonder if they are somehow fueling tumor regrowth. We are in the midst of figuring out if this is the case.”

Jezabel Rodriguez Blanco, Ph.D.

The Hedgehog pathway that she studies is a signaling pathway that’s important in the development of the nervous system. There are three hedgehog molecules – so named because when they were first discovered, a mutation along the pathway led to a fuzzy, hedgehog-like appearance on fruit fly larvae – that trigger the activation of this pathway. To differentiate them, each ligand was given a specific name – the other two were named for actual hedgehogs, while the Sonic Hedgehog ligand was named for video game character Sonic the Hedgehog.

In her last study, when the mice relapsed after a long period, her team discovered an unexpected population of treatment-resistant tumor cells that somehow resembled healthy cells of the nervous system. Likely, the similarity of these tumor cells to brain cells allowed them to evade therapies.

“When we analyzed those tumors, we saw an enrichment in cells that resemble healthy brain components,” she said. “These cells should not be in residual tumors, and we wonder if they are somehow fueling tumor regrowth. We are in the midst of figuring out if this is the case.”

In addition to the highly proliferative tumor cells, brain tumors also have small pools of cells that share similarities with the neurons, astrocytes and oligodendrocytes present in healthy brain tissues. These cells, which normally help with the functioning of the central nervous system, in tumor settings could be helping malignancies to persist after therapies. The mechanisms allowing them to evade therapies and facilitate the recurrence of the tumors remain unclear.

The Alex’s Lemonade Stand grant will allow Blanco to continue this investigation. She’ll be testing a combination of drugs to see if they will prevent relapse. She is hopeful that by targeting the drivers of the treatment-resistant cells, this therapy will not only banish the tumors, never to return, but also produce minimal side effects because of the more targeted approach.

“In theory, it should be less toxic than the standard of care that we are using,” she said. “We’re trying to help. We want children with cancer to have options; the options they actually deserve.”

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