CHLA Team Targets New Strategies for Difficult-to-Treat Pediatric Brain Tumors | Newswise

Newswise — A whiteboard displaying the long list of ongoing research studies in her lab is just one indication of how neuro-oncologist Jessica Tsai, MD, PhD, is leading the way in pediatric brain tumor research, along with her fellow physician-scientists in the Cancer and Blood Disease Institute at Children’s Hospital Los Angeles—the largest pediatric cancer program in the Western U.S.

Those projects involve two of the toughest-to-treat brain tumors in kids: atypical teratoid rhabdoid tumor (ATRT), which is the most common brain tumor in infants, and diffuse midline gliomas. Current treatments for ATRT are so intense that they can have devastating effects on children’s health, while diffuse midline gliomas have a median survival of just 12 months.

“Of all the pediatric cancers, brain tumors have some of the greatest needs for better therapies,” says Dr. Tsai. “Our team is exploring the genomic and epigenetic drivers of these tumors to find innovative strategies and more effective treatments.”

Searching for specific ATRT targets

Currently, babies and children with ATRT are treated with a mix of high-dose chemotherapy, an autologous stem cell transplant to replace bone marrow that is eliminated by the chemotherapy, and occasionally surgery, all of which can take a heavy toll. Patients can become severely immunocompromised, suffer infections and bleeding, and experience neurocognitive issues.

Dr. Tsai says that one of the challenges with ATRT is that very young children metabolize chemotherapy differently than older kids. And radiation in kids under 3 can cause devastating neurocognitive deficits.

Her team hopes to improve treatment options by making them much more targeted and specific to the tumor’s genetic underpinnings.

“These tumors have one known genomic driver, which is the deletion of a gene called SMARCB1 that is involved in remodeling the mix of DNA and protein called chromatin,” Dr. Tsai explains. “We also know from previous papers that there are three different subtypes of ATRT. There’s an opportunity to create therapies that are specific to SMARCB1 and ones that are tailored to treat tumor subtypes differently.”

Eliminating a nuclear export protein to kill ATRT cells

One project Dr. Tsai’s team is working on explores ATRT-associated genetic dependencies, genes that can be eliminated to kill cancer cells and would thus make good potential drug targets. “There’s a gene called exportin 1 that is a nuclear export protein, meaning that it carries proteins from a cell’s nucleus to the cytoplasm,” Dr. Tsai says. “We’ve shown in patient-derived ATRT cell lines that if you prevent exportin 1 from delivering all of its cargo by using CRISPR to get rid of the gene, it kills the ATRT cells.”

Tessa House, a technician in Dr. Tsai’s lab, is testing the effectiveness of six different drugs against exportin 1. “We’re hoping to gather enough preclinical data to move into a clinical trial,” Dr. Tsai explains.

Knocking out lipid metabolism genes to attack ATRT

Another project led by a postdoctoral fellow in Dr. Tsai’s lab, Stefania Tocci, focuses on data showing that ATRT tumors have high levels of expression of genes involved in lipid metabolism.

“Cancer cells can turn on genes that create many lipids, basically hijacking normal lipid metabolism to evade death and grow forever,” Dr. Tsai says. “Lipid metabolism relies on a complicated pathway, and we’re experimenting with knocking out certain genes in this pathway to kill cancer cells.”

House and Tocci are currently working on manuscripts and delivered oral presentations on their projects at the Pediatric Neuro-Oncology Conference, held May 15-17 in San Diego.

Using lipid nanoparticles to wipe out diffuse midline gliomas

Dr. Tsai’s lab is also investigating innovative approaches for diffuse midline gliomas (DMG), a highly aggressive pediatric brain tumor with poor survival.

The team has previously found that a transcription factor called FOXR2 is highly activated in these tumors. FOXR2 is a protein that regulates gene expression, but Dr. Tsai’s team has discovered that the transcription process starts in a different place in the gene than was previously thought.

“We’ve used CRISPR to shut off this regulatory region of the gene, and then we lose expression of FOXR2 and the cancer cells die,” Dr. Tsai says. “A technician in my lab, Marissa Coppola, is exploring how we can use this knowledge to effectively treat patients with DMG.”

Dr. Tsai’s team is working with CHLA’s Extracellular Vesicle Core to insert RNA molecules into tiny lipid nanoparticles, which previous data has shown are able to cross the blood-brain barrier, a notoriously challenging feat. “We’re experimenting with the nanoparticles to cross the blood-brain barrier and carry in the RNA, and eventually antibodies as well, that will target the cancer cells and block FOXR2 to kill these cells,” Dr. Tsai explains.

Considering these projects and others, Dr. Tsai is excited about her lab’s progress in tackling difficult-to-treat tumors. “I want to support everyone in my lab in testing their own ideas, and we all want our research to eventually impact patients,” she explains. “That’s why we do what we do.”

Learn more about the Cancer and Blood Disease Institute at CHLA.