UCSD researchers point to promising new drug target for glioblastoma

Non-tumorigenic glioblastoma cells (left) can spontaneously acquire cancer stem cell characteristics (right).--Courtesy of UCSD

New findings from researchers at the University of California-San Diego School of Medicine and Moores Cancer Center show that cancer stem cell properties are epigenetically controlled in glioblastoma, an aggressive and common form of brain cancer. And they believe their insights point investigators to a promising new drug target.

Cancer stem cells are responsible for driving the cancer metastasis in all types of cancers, especially in glioblastoma, associated with a high mortality rate. They generate heterogeneous populations of cancer cells that ultimately cause chemotherapy resistance--a major reason for recurrence in patients that undergo treatment for glioblastoma.

Senior author Clark Chen and his team at USCD published their work in Proceedings of the National Academy of Sciences using both mouse and human models. They demonstrated that an enzyme called lysine-specific demethylase 1 (LSD1) switched off the genes required to maintain cancer stem cell properties--which would explain how they can resist chemotherapy. And they picked out LSD1 as a target that can ultimately regulate tumorigenicity (the ability to spawn new tumors) and therefore the fate of the glioblastoma cancer stem cell.

Since LSD1 works epigenetically by controlling the expression of tumorigenic genes by removing chemical tags on DNA within the cancer stem cell, they demonstrated this could be reversed.

Chen commented that "this plasticity represents a mechanism by which the glioblastoma develops resistance to therapy. For instance, glioblastomas can escape the killing effects of a drug targeting MYC by simply shutting it off epigenetically and turning it on after the drug is no longer present."

The MYC gene is one of a few crucial genes glioblastoma cancer stem cells rely on for their tumorigenicity. Chen and his team's work casts light on the epigenetic control of these genes, offering a therapeutic angle in battling chemoresistance in glioblastoma.

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