Addy's cells continue to advance DIPG cancer research

SEATTLE, WASH. – When Addy "Boo" Trevino's parents Jen and Treay agreed to donate cells following Addy's initial brain tumor biopsy, they had no idea that gift would allow researchers all over the world the opportunity to continue to study their growth and test new treatments three years later.

Seattle Children's Hospital Pediatric Neuro-oncologist and Addy's doctor Nicholas Vitanza will soon be submitting the results of a study for peer review and publication in a scientific journal. The study is based primarily on Addy's cells and shows two new drugs that are active in treating Diffuse Intrinsic Pontine Glioma (DIPG), an incurable brain tumor. While Vitanza is encouraged with the findings, there are still many more questions to answer before the drugs could be used in clinical trials.

"You do this type of work all the time and there are 10 stories that don't work for every one that does. It was a much more likely end to the story that Addy's cells stopped growing eventually or the drugs didn't work at all," said Vitanza. "It turned out that it is kind of cool that Addy's tumor is hopefully going to get published and show that these drugs work."

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Addy, of Seeley Lake, was diagnosed with DIPG in June 2017 when she was three-years-old. Her parents chose to do the optional biopsy with the hope that her tumor would have a genetic mutation that would qualify her for an open clinical trial. The extra cells they donated to cell research.

Addy's biopsy cells were the first treatment naïve cells to grow in Dr. Jim Olson's Lab at the Fred Hutchinson Cancer Research Center, an associate of Seattle Children's Hospital. Treatment naïve cells have not been altered by radiation or chemotherapy. Of the 40 biologists in the lab, 10 work under Vitanza who is the principal investigator for the DIPG studies.

"What we learned from Addy has made our process possible to do it with others," said Vitanza.

Since Addy's biopsy, 50-75% of the treatment naïve cells that Vitanza has received from biopsies have grown. They now have five different treatment naïve DIPG models. Each model has a little variation and tell researchers a different story. While some grow well in the lab, others grow well in mice but not all grow both ways.

Addy's cells continue to grow very well in mice. Vitanza now has millions of cells frozen to use for future experiments. These cells will soon be available to other scientists studying DIPG in Switzerland and Arizona.

The first major study including Addy's cells involved 50 mice. Ten mice were placed in five different treatment groups. All 50 mice had Addy's tumor actively growing in their brain. Even though each group received a different treatment, all of the mice died around the same time.

"It didn't seem like any of the treatments were superior," said Vitanza. "We thought, maybe the drugs worked but they couldn't get into the tumor the way it grows in the brain."

Vitanza explained that the brain has a protective layer called the blood brain barrier, something not well understood. While typically aggressive tumors like DIPG cause the blood brain barrier to break down, Vitanza said DIPG maintains the "magical" barrier preventing things from getting in it.

With the hypothesis that the drugs actually do work to kill DIPG, they just couldn't get through the blood brain barrier, Vitanza along with scientists Matt Biery and Carrie Myers launched into a separate wing of investigation. They developed an animal flank study where they implanted Addy's cells into the soft tissue in the side of 30 mice. Even though the Addy's cells were from a brain tumor, they grew very well in the flanks.

Vitanza said there were two main benefits to the flank study. First, researchers could feel the tumor grow in size making it easy to measure. Second, the placement also eliminated the blood brain barrier, no longer limiting the effects of the drugs on the DIPG tumor.

There have already been studies showing that the epigenetic class of drugs can be beneficial. Of the 20 drugs in the class that have been previously tested, only two of them worked. However, Vitanza said they have not been studied in mice with DIPG tumors before.

In the first brain study, neither showed measurable results. However, the results from the flank study showed that the tumors treated with the drugs stopped growing almost completely while the group with untreated flank tumors grew exponentially.

Vitanza said when they studies the free-floating cells, the drug killed the DIPG cells. However after 75 days of treatment and then discontinuing the drugs, the flank tumors began to regrow.

"The two drugs in the flank model work really well," said Vitanza. "The problem is not that the drugs don't kill DIPG cells. It seems like the drugs don't get into the brain very well. This is hopefully a problem that can be solved."

Vitanza said he hopes to continue to research what drugs combine well with the two epigenetic drugs and further investigate why they didn't work in the brain model. He has always been a big proponent that DIPG is not a tumor they are going to kill with one drug.

"The goal of publishing that these drugs are effective is not for them to become clinical trials and try them one at a time," said Vitanza. "What I hope is that the next generation will combine these drugs with other studies and potentially have a clinical trial with these drugs combined with something else."

Vitanza is also hoping to use Addy's model to test different Car T-cell targets in DIPG and incorporate their DIPG models into their immunotherapy program at Seattle's Children's Hospital. However that takes funding.

Erin Cordry, founder of the Pediatric Brain Tumor Research Fund (PBTRF), a member of Seattle Children's Guild Association, said that even in a good economy, less than four percent of all cancer funds are allocated to pediatric research.

In the past 15 years, the PBTRF has raised over $6 million with 100 percent of the funds going to pediatric brain tumor research. They started the annual Run of Hope Seattle in 2009 with the Four Seasons Hotel and it have become the biggest fundraiser for pediatric cancer research in the Pacific Northwest. The event typically attracts around 2,000 people to the run in Seattle's Seward Park. This year the gathering has been canceled due to COVID-19 and a virtual Run of Hope has been scheduled for Sept. 27.

This is the biggest fundraiser that supports the research done by Vitanza, Dr. Jim Olson, Dr. Sarah Leary, Dr. Courtney Crane and Dr. Mike Jensen.

"I think it is a pretty special group of networking researchers here in Seattle," said Cordry. "They are a collaborative, they work together and they inform each other's research."

Vitanza said if his funding is significantly reduced due to the pandemic, it will definitely affect their lab work not only this year but for years to come.

"The entire future of finding cures for kids depends on philanthropy," said Cordry. "If we don't have the money, we don't have the people to do the research and research is expensive."

For more information about PBTRG, to donate to pediatric brain research or to learn more about the Run of Hope visit https://www.pbtrf.org/. Donations can also be made by mailing a check to Pediatric Brain Tumor Research Fund P.O. Box 9784, Seattle, WA 98109.