Researchers at Cincinnati Children’s are exploring the safety and early efficacy of molecular targeted therapy for diffuse intrinsic pontine glioma (DIPG) and high-grade glioma (HGG) tumors in a clinical trial that also could expand the availability of tumor tissue for future study. DIPGs are aggressive tumors that arise in the brain stem and are not amenable to surgical resection. HGG are aggressive tumors outside of the brain stem. No major advances have been made in the treatment of children with DIPG and HGG for several decades, despite clinical trials testing a multitude of chemotherapeutic agents. These tumors remain the leading cause of brain cancer death in children and young adults.

The early phase II trial is currently evaluating the safety and long-term feasibility of using radiation therapy followed by a developmental drug called ribociclib to treat newly diagnosed DIPG and HGG. Enrollment for this study is open, and participants are receiving the experimental therapy.

Ribociclib is an orally bioavailable cyclin-dependent kinase inhibitor known to shut down the activity of CDK4 and CDK6, molecules that drive cell division. However, the drug requires the tumor to have the presence of retinoblastoma (RB), a tumor suppressor protein. Study participants with HGG will undergo surgical resection or biopsy pending the location to confirm the presence of RB, and participants with DIPG will have the option of having a stereotactic biopsy to confirm the presence of RB and histological classification. A biopsy is optional for participants diagnosed with DIPG, since over 70 percent of patients with DIPG have been reported to have an intact RB.

Addressing a grave limitation of DIPG research 

Researchers hope that many participants with DIPG undergo the biopsy, since the tissue samples could yield valuable information about these rare and uniformly fatal tumors. Efforts to study and implement safe surgical techniques for brainstem biopsy, which were pioneered in Europe, have recently been accepted in the United States.

“Historically, DIPGs have not been routinely biopsied at diagnosis because the tumors have a very characteristic appearance on MRI,” says Charles Stevenson, MD, a pediatric neurosurgeon at Cincinnati Children’s and co-investigator on the study. “An unintended consequence of this diagnostic approach was a dearth of tissue samples, which limited what researchers could learn about the molecular biology of DIPG.”

A collaborative effort 

The study is a joint venture of the Cancer and Blood Diseases Institute and Division of Neurosurgery at Cincinnati Children’s. The principal investigator is Mariko DeWire, MD, a pediatric neuro-oncologist at Cincinnati Children’s, whose previous DIPG research has emphasized the use of biopsy from autopsy. She began developing the ribociclib study about four years ago, building on seminal publications regarding the genomics of DIPG. Recently, genomic sequencing studies yielded insight into the genomic framework of pediatric DIPG and HGG, uncovering alterations of checkpoint cell cycle regulators (CDK4/6, CDK2NA) and activation of the PI3K/Akt/mTOR pathway. Joint inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) is promising due to strong biologic rationale, non-overlapping single-agent toxicities, and preliminary clinical experience in adults that suggests tolerability of this combination. Thus, a phase I study of ribociclib and everolimus following radiation therapy in children with newly diagnosed non-biopsied DIPG and RB+ biopsied DIPG and HGG is underway; enrollment began in the fall of 2017. 

In 2012, Cincinnati Children’s established the International DIPG Registry under the direction of Maryam Fouladi, MD, an expert pediatric neuro-oncologist and the medical director of the Cincinnati Children’s Brain Tumor Center. The International DIPG Registry, a collaborative effort of physicians and researchers from North and South America, Canada, Europe and Australia, centralizes and standardizes the collection of clinical, imaging, data and tumor samples from DIPG patients. Fouladi is the registry’s principal investigator.

“As biopsies become more common, and as more tissue from autopsy has been donated in recent years, the pace of DIPG research in the lab is increasing exponentially,” Stevenson says. “Families participate because they know how important the study of tumor tissue is in finding effective therapies for DIPG.”