Researchers in the Preston Robert Tisch Brain Tumor Center at Duke have identified a new therapeutic vulnerability in IDH-mutant astrocytomas and other gliomas.
Alternative lengthening of telomeres (ALT) is a cancer-specific mechanism that enables unlimited tumor cell division. The Waitkus Lab found that ALT-positive tumors are dependent on an enzyme called SMARCAL1 to survive. When SMARCAL1 is inhibited, ALT-positive glioma cells sustain catastrophic DNA damage and die while other types of tumor cells are largely unaffected.
“Our findings suggest that patients whose tumors use ALT, including IDH-mutant astrocytomas and several subtypes of aggressive pediatric gliomas, may benefit from therapies that selectively disrupt SMARCAL1 activity,” said senior author and Duke Neurosurgery faculty Matthew Waitkus, PhD. “Because ALT is not activated in healthy tissues, targeting this pathway has the potential to be more tumor-specific and less toxic than conventional therapies.”
About 10-15% of all cancers, along with nearly 100% of IDH-mutant astrocytomas, activate ALT.
Waitkus’s team is working to better define which patients are most likely to benefit from this approach by refining biomarkers of ALT and understanding how to use SMARCAL1 targeting with IDH-mutant inhibitors and immunotherapies.
“Collectively, these efforts will help guide the development of future anti-cancer drugs targeting SMARCAL1 to exploit this vulnerability in brain tumors,” Waitkus said.