Fred Hutch–led team receives $6M to study deadly brain tumor

Ependymomas are brain tumors that arise from glial cells, which surround neurons and help support their function. Dr. Eric Holland of Fred Hutchinson Cancer Research Center heads a project funded by a new $6 million, five-year, multi-institutional grant from the National Cancer Institute to explore the biology of a type of ependymoma driven by a hallmark gene fusion. The aim is to develop improved treatments that target the gene fusion.

Gene fusions occur when a major DNA rearrangement results in two genes becoming attached, which can create a new protein with cancer-promoting activity. The fact that a single, specific genetic change is driving these tumors may mean that a therapy focused on that specific change could work, Holland said. By combining expertise in cancer biology, preclinical models and drug discovery, the team hopes to make substantial progress toward that therapy.

Hallmark gene fusion drives supratentorial ependymomas

Ependymomas are the third most common brain and spinal cord tumor in children, though they occur in both children and adults. There’s currently no tailored treatment for people with ependymomas, who are all treated with some combination of surgery, radiation and chemotherapy. In general, a patient’s prognosis varies by the location of their tumor, their age and their tumor stage, but about 65% of adult patients and 60% of pediatric patients survive five years past diagnosis.

Ependymomas that occur above the tentorium — the membrane that separates the upper two-thirds of the brain from the lower third — are called supratentorial ependymomas. Most supratentorial ependymomas carry a characteristic DNA rearrangement in which a gene known as RelA becomes fused to a gene of unknown function called C11orf95.

The gene fusion arises when one section of DNA is catastrophically mangled and then haphazardly patched back together. Supratentorial ependymomas with the RelA-C11orf95 gene fusion have few other mutations.

This kind of singular genetic change is very likely to be the driving force behind a tumor, Holland said. Sure enough, he and collaborator Dr. Richard Gilbertson at the University of Cambridge, whose team initially discovered the RELA-C11orf95 fusion, showed that RELA-C11orf95 by itself was enough to trigger ependymomas in mice.

Major opportunity, major challenges

The fact that RelA-C11orf95 alone can promote cancer development makes it pretty powerful — but it could also be the supratentorial ependymoma’s secret vulnerability. RelA-C11orf95 gets the tumor started and keeps it running, but there’s no backup power source. In theory, Holland explained, a therapy that interferes with the protein encoded by this Franken-gene could be all that’s needed to stop the tumor in its tracks.

A prime example of a gene fusion being the both the source of a tumor’s power and its undoing is Bcr-Abl. This gene fusion is enough to cause chronic myeloid leukemia and is famously the target of Gleevec (imatinib mesylate), the drug that transformed CML from a death sentence into a manageable condition.

In the case of RelA-C11orf95, the problem is that while the fusion presents a major therapeutic opportunity, it also presents some major challenges. Certain types of protein functions are easier to disrupt than others, and RelA, unfortunately, is one of those that’s difficult to target. The unknown function of C11or95 presents its own problem.

To overcome these challenges, Holland is teaming up with Gilbertson and other researchers with world-class expertise in cancer biology and drug discovery. Joining Holland and Gilbertson are two collaborators from the University of California, San Francisco: Dr. William Weiss, an expert in understanding neural cancer biology, and Dr. Kevan Shokat, an expert in medicinal chemistry and creative approaches to drug discovery.

Together they will seek novel therapeutic targets for supratentorial ependymomas by working to understand how the fusion protein promotes tumor development and progression, and how it could potentially be targeted. The team will also seek potential new drugs that inhibit the RelA-C11orf95 fusion protein or other proteins it regulates in its role as a tumor promoter.

The grant, known as a U54, supports not merely the experimental work, but the exchange of ideas so crucial to scientific discovery, Holland said: “It pushes the field forward.”