A subtype of juvenile glioma responds to a CDK4/6 inhibitor

“We’re finally starting to see more targeted therapies for different forms of brain cancer,” says senior author Mariella Filbin, MD, PhD, co-director of the Brain Tumor Center of Excellence at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and research director of the Pediatric Neuro-oncology Program at Dana-Farber. “Our patients really need these new treatment options.”

The study was published in Cancer Cell.

High-grade gliomas are the leading cause of cancer deaths in children and adolescents. There are few effective therapies for these tumors, and only about one-fifth of children diagnosed with high-grade gliomas survive beyond five years.

A high-grade glioma subtype, called diffuse hemispheric glioma H3G34R/V-mutant (DHG-H3G34), typically occurs during adolescence and accounts for about 30% of high-grade gliomas in children. Before these studies, these tumors were thought to arise from glial cells, which provide a scaffold for signaling neurons in the brain.

Filbin and her team found, surprisingly, that cancer cells more closely resemble neurons. The team made this discovery using single-cell multi-omics sequencing—analysis of active genes and proteins in individual cells in tumor samples.

“Once we know what cells we’re working with, we can start looking at therapeutic vulnerabilities,” Filbin says.

To uncover these vulnerabilities, Filbin’s lab initiated a CRISPR study of these neuron-like cancer cells. The study turns off genes one by one in the human genome to determine whether any of the 20,000 genes are essential for cell survival. They found several vulnerabilities, many of which are specific to neuron-like cancer cells. But most of these genes are not yet targeted by any known drugs.

The study also pointed to CDK6 as a key vulnerability. CDK6 is a gene that regulates the cell division cycle and plays a major role in cell fate decisions as cells differentiate. Several CDK4/6 inhibitors have already been approved to treat other cancers, such as breast cancer.

Shortly after the study was completed, Filbin learned that the lab of co-author Chris Jones, PhD, at the Institute of Cancer Research in London had conducted a similar CRISPR study with similar results. “We teamed up and combined our data,” Filbin says.

The next step was to test CDK4/6 inhibitors in patient-derived tumor models. There are no public repositories for this rare form of brain cancer, so all samples tested came from patients who were treated at Boston Children’s Hospital and at hospitals in Vienna, London, Rome, Hamburg, and Munich.

The team first confirmed that three CDK4/6 inhibitors, ribociclib, palbociclib, and abemaciclib, could cross the blood-brain barrier. However, ribociclib had several advantages, including better tolerability at higher concentrations and greater specificity for CDK6. In mouse models with patient-derived xenografts, ribociclib treatment slowed tumor growth and prolonged survival.

When co-author Fernando Carseller, MD, PhD, of the Royal Marsden Hospital, heard about the work, he contacted Filbin. He had a patient, a 13-year-old whose cancer had returned twice. There were no more treatment options available. Ribociclib had been tested in clinical trials in children before, so the team had the dosing and safety data they needed to administer the drug safely.

After ribociclib treatment, the patient’s cancer remained stable for 18 months. Filbin and Karen Wright, MD, MS, a clinician-scientist in the Brain Tumor Center at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, are now working with the Connect Consortium, the Collaborative Network for Neuro-oncology Clinical Trials, to initiate a global clinical trial of ribociclib in patients with this subtype of high-grade glioma before any other treatments are tried.

“We want to see how monotherapy works before a relapse occurs,” Filbin says.

But treatment likely won’t be enough to cure. Filbin and Jones have learned from their research that inhibiting CDK6 doesn’t always kill cancer cells. Instead, it sometimes causes a break in the cell cycle that allows the cells to continue to differentiate into neurons—but not in a good way.

“These are misfiring neurons, and they’re still cancer cells,” says Filbin, who is now focused on finding additional drugs that could be combined with ribociclib to treat cancer more effectively.

“We’re at a point where we’re starting to see positive effects from a single drug,” Filbin says. “Just like we did with leukemia decades ago, when one drug had little effect, we started putting multiple drugs on top of each other and now we have very high cure rates in children with leukemia, so that’s our hope.”