Alzheimer-Related Protein Suppresses Gliomas

Tau, the microtubule-associated protein linked to neurodegenerative disease, plays a critical role in brain cancer, too. Researchers report that mutant IDH triggers tau expression, which in turn inhibits EGFR signaling to impede glioma progression (Sci Transl Med 2020; 12:eaax1501).

The findings help explain why IDH1/2 mutations are linked to prolonged survival—and EGFR mutations to poorer outcomes—in people with glial brain tumors. They also provide a scientific rationale for pharmacologically mimicking tau's function with microtubule-stabilizing drugs to treat IDH–wild-type brain cancers or low-grade gliomas lacking EGFR mutations.

Taxanes inhibit microtubule disassembly by binding the same site as tau. Most approved taxanes do not readily cross the blood–brain barrier, but some newer agents do. “If our data using mouse models translates into patients,” says Pilar Sánchez-Gómez, PhD, of the Carlos III Health Institute in Madrid, Spain, who led the new study, “these drugs, at low concentrations, may put the brakes on the disease.”

Over the past 15 months, independent teams led by Sánchez-Gómez and George Blanck, PhD, of the University of South Florida in Tampa reported that gliomas expressing high levels of MAPT, which encodes tau, have better clinical prognoses (Front Aging Neurosci 2019;11:231; Oncology Reports 2019;41:1359–66). Those findings were entirely phenomenological until Sánchez-Gómez's latest paper. “They were able to add mechanism,” Blanck says.

Sánchez-Gómez and her team used tissue samples, cell lines, and mouse models to interrogate the connections between tau activity and favorable IDH1/2 mutations or adverse EGFR mutations in gliomas.

In IDH1/2-mutant gliomas, they observed high levels of tau that decreased as tumors acquired aggressive properties. In EGFR-mutant gliomas, however, tau expression was negligible. Probing the molecular links, the researchers showed that mutant forms of IDH serve as epigenetic regulators of MAPT transcription. By increasing methylation at a particular site in the MAPT gene, the mutant enzymes disrupt the normal binding of a repressive transcription factor, leading to elevated expression.

Tau then—through its stabilizing effects on microtubules and the subsequent changes in intracellular trafficking of proteins and organelles—promotes EGFR degradation. Without active EGFR signaling, glioma cells do not undergo mesenchymal transformation and they stay in a less aggressive state.

Tau-induced repression occurred even when EGFR was amplified but otherwise unaltered—and the same effect could be achieved therapeutically with epothilone D (Bristol-Myers Squibb), a brain-penetrating taxane no longer in clinical development. However, gliomas with activating mutations in EGFR no longer responded to tau. As Sánchez-Gómez and her colleagues reported, the EGFR pathway—despite high levels of tau—remained in overdrive, spurring the growth of new blood vessels and decreasing the sensitivity of cancer cells to chemotherapy and radiation.

According to Sánchez-Gómez, the findings also provide a cautionary note regarding mutant-selective IDH inhibitors to treat gliomas (Cancer Discov 2019;9:992). These agents may stop oncogenic forms of the IDH enzyme from producing a cancer-causing metabolite, but they may also suppress tau activity—which could explain why IDH1-mutant cell lines treated with a precursor to vorasidenib (Agios) were less sensitive to other therapies.

“If you actually target IDH mutations you can make a tumor much more aggressive,” Sánchez-Gómez warns. “That's a danger with these kinds of treatments.” –Elie Dolgin

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