UCSF study sheds light on new treatments for meningioma patients

Doctors surgically remove meningiomas and then radiate the surrounding tissues, but these brain tumors often come back. At that point, clinicians can only offer patients repeat surgery or repeat radiotherapy, which grow increasingly risky with each treatment course.

Researchers at UC San Francisco have now identified a biomarker that distinguishes molecular groups of meningiomas with distinct clinical outcomes, biological drivers, and therapeutic vulnerabilities.

Their results, published in Nature Genetics, suggest a potential therapeutic strategy using cell cycle inhibitors, a class of drugs already approved for treating other cancers. Moreover, their findings indicate these medications may be helpful for meningiomas that are resistant to surgery or radiotherapy.

“So much of the problem of developing a new cancer drug begins with understanding the fundamental biology of cancer itself,” said senior author David Raleigh, MD, PhD, an assistant professor in the UCSF Departments of Radiation Oncology and Neurological Surgery.

Many targeted cancer therapies focus on whether certain DNA mutations present in the tumor affect tumor growth or drug resistance. But previous studies show that these types of DNA mutations are not common in meningiomas.

Rather than looking at DNA mutations in meningiomas, Raleigh and his colleagues examined the architecture of the DNA in these common tumors. Modifications to the DNA architecture — like DNA methylation — can influence the way tumors grow or respond to therapy.

Through a multidisciplinary effort, the scientists were able to group meningiomas into three distinct categories based on DNA methylation patterns. The researchers — led by UCSF Medical Scientist Training Program student Abrar Choudhury, PhD — then found that drugs inhibiting the cell cycle were most effective at blocking the growth of meningiomas that had intermediate or severe clinical outcomes.

“Of the groups we discovered, these are the two where we need new therapies,” Raleigh, who is also the Halperin Endowed Chair in Meningioma Research, said.

Two recently published clinical trials suggested that immunotherapy may not be effective for meningiomas. Raleigh and his colleagues think now they may have found out why.

This UCSF study reveals that even though meningiomas may contain many immune cells, these cells are largely inactive.

“Current immunotherapy strategies basically take the brakes off of the immune system,” Raleigh said. “But it appears the immune cells in the meningioma microenvironment weren't going anywhere to begin with, so taking their brakes off might not provide much of a benefit.”

The differences in DNA methylation status of these tumors do not track with the current categories the World Health Organization uses for diagnosing meningiomas.

This finding, Raleigh said, might help explain why some meningiomas that look benign under the microscope do not behave as such in the clinic while others that seem like they would be aggressive may be unexpectedly well-controlled with existing therapies.

The DNA methylation status of meningiomas could help doctors identify which tumors are likely to reappear after they are treated with surgery. Raleigh hopes this study will help make this type of testing more widely available to meningioma patients. To that end, he and his colleagues have created a free online resource that allows other researchers to upload the DNA methylation profile of meningiomas to classify the tumors by subtype.

Raleigh and his colleagues are now looking towards starting new clinical trials for meningioma patients at the UCSF Brain Tumor Center and other institutions.