Researchers at The University of Texas Health Science Centre at San Antonio have discovered a way to delay or even block recurrence of the deadliest brain cancer after radiation, bringing new hope for survival.

Ironically, the scientists found that the customary treatment for glioblastoma, ionising radiation, can also cause tumours to recur, by generating senescent or aged cells that secrete molecules that can spur growth of neighbouring cancer cells.

But they discovered that a new class of experimental “senolytic” drugs, given after radiation, can kill those senescent cells while sparing normal ones, thereby stemming recurrence.

A senolytic refers to a novel class of small molecules thought to selectively induce death of senescent cells.

“These findings lend credence to the ‘one-two punch’ approach to radiation therapy, where radiation or other agents are first used to induce senescence in a tumour, and then the senescent cells are removed by a senolytic,” said Sandeep Burma, PhD, professor and vice chair (research) of neurosurgery at UT Health San Antonio and its Mays Cancer Centre.

Burma and Bipasha Mukherjee, PhD, associate professor of neurosurgery at UT Health San Antonio, are lead authors of the study, “Targeting cIAP2 in a novel senolytic strategy prevents glioblastoma recurrence after radiotherapy,” published Feb. 19 in the journal EMBO Molecular Medicine.

Other authors also are with the departments of neurology, biochemistry and structural biology, and medicine at UT Health San Antonio, as well as the University of Texas Southwestern Medical Centre in Dallas, and the Mayo Clinic of Rochester, Minnesota.

A double-edged sword

Recurrence of glioblastoma, the most common primary brain tumour in adults, is a major clinical problem as it occurs quickly and can be even more aggressive.

Accordingly, Burma’s lab has focused on understanding the forces driving recurrence and strategies to block the process.

Specifically, they are trying to understand whether senescence of cancer cells after radiation therapy – also called therapy-induced senescence, or TIS – might counterintuitively be driving recurrence.

Burma said that ionising radiation, which is routinely and, in many cases, effectively used to treat cancer, is a double-edged sword since radiation also is a powerful carcinogen.

For glioblastoma, radiation is still the most effective therapy.

But radiation exposure also is the only known risk factor for its development, and could perhaps also drive recurrence.

When a tumour is radiated, a cancer cell can either die or remain alive but be permanently unable to divide further, a state called senescence, with both outcomes controlling tumour growth.

However, researchers in this study discovered that senescent glioblastoma cells secrete large amounts of growth factors and other molecules that can act on persisting cancer cells and encourage them to re-proliferate.

What could be done about this problem?

End of senescence

Senolytic gets its name from the words “senescence” and “lytic,” or destroying.

The researchers found that senescent glioblastoma cells rely on an anti-apoptotic protein, or one that slows or prevents cell death known as cIAP2, for survival.

They also found that targeting cIAP2 with a senolytic drug called birinapant in mouse tumour models after radiation could kill senescent cells while sparing normal cells.

They tested their approach in multiple mouse models of glioblastoma and found that while the drug was not effective on its own, it was very effective at delaying or even preventing recurrence if given as an “adjuvant” after radiotherapy.

“These pre-clinical results highlighting a novel senolytic approach for glioblastoma are very exciting from a clinical standpoint as they clearly indicate that significant improvement in patient survival may become possible by eliminating senescent cells arising after radiotherapy,” Burma concluded.

Targeting cIAP2 in a novel senolytic strategy prevents glioblastoma recurrence after radiotherapy

Nozomi Tomimatsu, Luis Fernando Macedo Di Cristofaro, Suman Kanji, Lorena Samentar, Benjamin Russell Jordan, Ralf Kittler, Amyn A.Habib, Jair Machado Espindola-Netto, Tamara Tchkonia, James L.Kirkland, Terry C.Burns, Jann N.Sarkaria, Andrea Gilbert, John R.Floyd, Robert Hromas, Weixing Zhao, Daohong Zhou, Patrick Sung, Bipasha Mukherjee, Sandeep Burma

Source: University of Texas Health Science Center at San Antonio