This story originally appeared on bwhclinicalandresearchnews.org

More than 10 years ago, Tracy Batchelor, MD, Chair of the Department of Neurology at Brigham and Women’s Hospital, and Chuck Stiles, PhD, formerly Co-Chair of the Department of Cancer Biology at Dana-Farber Cancer Institute (DFCI), received a large grant from the National Cancer Institute (NCI) for a Specialized Program of Research Excellence, or SPORE to work collaboratively to pursue new therapies for glioma. Today, those efforts are bearing fruit.

This spring, in the latest example of success that has emerged from the SPORE, the Food and Drug Administration granted accelerated approval of the oral drug tovorafenib, a RAF inhibitor, for relapsed or refractory pediatric low-grade gliomas harboring a BRAF fusion or rearrangement, or BRAF V600 mutation. Low-grade gliomas are the most common glioma of childhood and BRAF alterations are found in roughly 75% of these tumors. Accordingly, a medical therapy for this tumor type has potential for great impact.

For investigators who are a part of the Targeted Therapies for Glioma SPORE, which brings together researchers from across Brigham and Women’s Hospital, Massachusetts General Hospital, Dana-Farber Cancer Institute, and Boston Children’s Hospital, the approval represents the importance of collaboration among institutions, scientists, and physicians in research and clinical settings. The NCI initially granted $12.5 million for the Boston-based SPORE group in 2013 and has since renewed funding twice. The group is now heading into its eleventh year and will continue to fund and nurture early-stage projects, like the one that led to tovorafenib.

“This is the right way to do it. It’s team-based science,” said Batchelor, who is also the principal investigator of the SPORE grant.

Daphne Haas-Kogan, MD, chair of Radiation Oncology for Mass General Brigham and a co-leader of the SPORE, said the collaborative work done across the labs benefits children not only locally, but all over the world.

“It is so deeply thrilling and heartening to see how close collaborations across specialty groups, from basic scientists to translational clinicians, have led to such impactful, practice-changing discoveries,” Haas-Kogan said.

Breaking Through the Barrier

The approval of tovorafenib is a success story nearly a decade in the making. The path to tovorafenib started with a Developmental Research Project, an internal award from the SPORE grant, intended to spark research that could someday blossom into a full SPORE project.

Mark Kieran, MD, PhD, who was the director of Pediatric Neuro-oncology at Dana-Farber at the time, was working with Michael Eck, MD, PhD, of Dana-Farber and Stiles, who was then a professor at Harvard Medical School and Dana-Farber.

They applied and received funding to screen a large panel of small molecule RAF inhibitors—drugs that have been shown to help adult patients with other forms of BRAF mutant cancer—to identify candidate drugs with a high chance of being able to break through the blood brain barrier.

“When it comes to brain tumors, it’s not even worth thinking about a drug unless you can show it can get to the brain,” Stiles said.

Nathalie Agar, PhD, an investigator in the Brigham’s Department of Neurosurgery, with an appointment at DFCI, is also a member of the SPORE. She developed the imaging technique which showed that this drug, then known as MLN2480, could cross the blood brain barrier in animal models.

“Other drugs didn’t distribute very well,” Agar said. “They would treat some of the cancer cells but would still leave some behind that would essentially keep supporting tumor growth.”

The small molecule that would eventually be known as tovorafenib showed evidence of targeting more cancer cells.

Keith Ligon, MD, PhD, chief of Neuropathology at the Brigham and an investigator at DFCI, was a postdoctoral fellow in pediatric oncology at Dana Farber when he first started studying biomarkers of gliomas in children and adults. He joined the SPORE to further his work developing diagnostics and pediatric testing for tumors. He is now the director of the SPORE molecular pathology core.

Ligon said the work across institutions within the SPORE group was critical to launching the drug into phase 1 clinical trials.

“Sometimes people are tempted to say, ‘Let’s not collaborate’ and are worried about clinical boundaries,” Ligon said, “but those boundaries don’t exist in research.”

‘A Remarkable Feat’

The preclinical work done in the SPORE group led to a phase 1 investigator-initiated clinical trial, which was initially led by Kieran in collaboration with Karen Wright, MD, MS, a pediatric neuro oncologist at DFCI and Boston Children’s Hospital. Wright took over as project lead after Kieran moved to a new position outside Harvard.

“his work highlights the amount of preclinical and clinical effort involved in such a discovery,” Wright said. “This is a great example of academia and industry working toward a common goal.”

In that study, six of the first nine treated children with refractory or recurrent pediatric low grade astrocytomas had radiographic regression of their tumors after treatment with tovorafenib. From there, a company, Day One Biopharmaceuticals acquired the drug for phase 2 and 3 trials. Day One’s continued efforts set the stage to apply for FDA approval.

“It is exceedingly challenging to achieve approval of new agents for pediatric cancers and this is truly a remarkable feat,” Haas-Kogan said.

Batchelor added the FDA approval is an example of how the SPORE program’s work can lead to improved outcomes for brain tumor patients. He said the work in the SPORE is far from over.

Based on the success of the SPORE to date, the grant was renewed in 2024.

“In the next five years, the project team will begin to look at why some of these low-grade astrocytomas respond and some do not,” Batchelor said. “The team will also use artificial intelligence methods to examine MRI scans of children treated with tovorafenib to see if any patterns predicting response or resistance can be detected.”

Beyond Tovorafenib

The project that led to tovorafenib’s discovery is just one of three Boston-based projects funded by the NCI SPORE grant. Each project focuses on a different type of glioma.

“We’re studying gliomas that have specific genetic alterations where it might make sense to use a targeted drug,” Batchelor said.

Two other projects will be the focus of the SPORE group over the next five years. One project will study potential targeted therapeutic treatments for diffuse midline gliomas, a tumor Batchelor said is notoriously treatment resistant. The other will be a continuation of work being done on Isocitrate dehydrogenase (IDH) mutant gliomas, something Batchelor described as an “Achilles heel” of gliomas.

Batchelor said the SPORE has also been a critical tool to support junior faculty and trainees studying gliomas through its Career Enhancement Program. The SPORE leaders have also received two NCI Diversity Supplement Awards to support early career work for talented scientists from underrepresented groups who are starting their academic careers in neuro-oncology.

“Without the SPORE, none of this work would have been possible,” Batchelor said. “This grant is a catalyst for driving foundational work between institutions and in supporting the next generation of scientists working to cure glioma.”

Disclosures: Karen Wright and Daphne Haas-Kogan are inventors on this patent application titled, “Raf inhibitor for treating low grade glioma.” Day One is a co-owner of the patent application.