An enzyme called ADAM10 cleaves a protein found in synaptic membranes, creating a soluble factor that can fuel the growth of brain tumors. Blocking this enzyme shrinks tumors in xenograft models of pediatric glioblastoma and diffuse intrinsic pontine glioma, two brain cancers with few to no effective drug options, researchers reported at the American Academy of Neurology 2017 Annual Meeting.

The recent discovery that gliomas can commandeer neuronal activity in their microenvironment has yielded a therapeutic drug lead.

By blocking the release of a membrane protein normally involved in synaptic transmission but that can be hijacked by brain tumors for their own advantage, a team led by Michelle Monje, MD, PhD, of Stanford University in California, robustly inhibited the growth of two intractable pediatric cancers in xenograft mouse models.

Monje presented the research at the American Academy of Neurology 2017 Annual Meeting in Boston, MA, on April 24.

“She showed unequivocally that there is the potential for therapeutic value by inhibiting this pathway,” said Tracy Batchelor, MD, a neuro-oncologist at Boston's Massachusetts General Hospital, who was not involved in the research. “I do believe that Dr. Monje and her colleagues are on the threshold of entering clinical trials.”

The new data build on an earlier report from Monje demonstrating that active neurons promote growth of glioma cells with a soluble factor called neuroligin-3. Usually, neuroligins anchored in the postsynaptic membrane help form connections between neurons at excitatory synapses. However, enzymes sometimes cleave neuroligins to create the secreted signal that Monje and her colleagues showed was a driving force behind glioma cell proliferation. Looking at more than 400 adult glioblastoma samples, the researchers also found an inverse relationship between neuroligin-3 expression and survival.

Monje's team then searched for the enzyme responsible for neuroligin-3 cleavage. They first created a shortlist of candidates by looking at neuroligin-3's amino acid sequence at the cleavage site. They then used chemical inhibitors and mouse knockout models to narrow in on ADAM10, a so-called sheddase enzyme that lops off neuroligin-3 from neurons and oligodendrocyte precursor cells. In mice implanted with patient-derived glioblastomas or diffuse intrinsic pontine gliomas, an ADAM10 inhibitor “robustly stagnates tumor growth,” Monje said, adding: “We hope that we're able to translate these findings soon.”

The idea of targeting the tumor microenvironment in the brain is “very unique,” said Mariella Filbin, MD, PhD, a pediatric neuro-oncologist at Boston's Dana-Farber Cancer Institute, who has collaborated with Monje but was not involved in the ADAM10 study. Most brain cancer researchers “just focus on the tumor cells,” Filbin noted, but Monje “is looking at how to target the interactions between the tumors and all these other cells—astrocytes, neurons, microglia, oligodendrocytes. That's the beauty of her work.”

There is some precedent for blocking ADAM10 pharmacologically. In 2005, Incyte began testing the ADAM10 inhibitor INCB7839, taking the drug through phase II trials in women with HER2+ metastatic breast cancer. The strategy was to delivery INCB7839 in combination with trastuzumab (Herceptin; Genentech/Roche), with the hope that the ADAM10 inhibitor would reduce cleavage of HER2 and boost response rates to the anti-HER2 drug.

Data presented in 2010 showed that women who received INCB7839 had lower HER2 levels. However, additional tissue analyses failed to confirm the clinical findings and Incyte suspended further development. –Elie Dolgin

©2017 American Association for Cancer Research.
2017
American Association for Cancer Research.