CRISPR Treatment Developed Against the Protein Enabling Unlimited Growth in the Brain Tumor GBM

The 10 hallmarks of cancerinclude the capacity for unlimited proliferation. Most cancer cells have, in genes enabling unlimited division, mutations present. In September 2018, Cancer Cellpublished a study in which CRISPR stopped the activity of a gene enabling unlimited proliferation in 50 different cancer types, including the brain tumor glioblastoma (GBM). This study may pave the way for revolutionary treatments for aggressive tumors such as glioblastoma.

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The research examined cells obtained from a GBM patient. GBM tumors with TERT promoter mutations were found to depend on the GABP protein for proliferation. TERT, telomerase as it is also known, is an important enzyme. Cancer cells lengthen their telomeres by maintaining high telomerase activity, allowing unlimited proliferation. The study found that a part of the GABP protein called GABPbeta1L activates the telomerase gene. Researchers therefore removed only one part of the protein (GABPbeta1L), using CRISPR to eliminate it.

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According to the results, tumor growth slowed substantially in animal models in which the gene segment called GABPbeta1L was eliminated with CRISPR.

GABP is a protein with many functions in healthy cells. Blocking its activity could cause serious adverse effects in the body. GABP lacking this segment was found to have a lethal effect in cancer cells without harming normal cells.

What Does This Study Mean for Us?

• This study identified an important drug target for aggressive GBM and other cancers with TERT mutations.
• % 83 of GBM tumors have TERT promoter mutations. Drugs targeting telomerase cannot yet be used because they have been found highly toxic in humans. This study may pave the way for brain tumor treatments with few adverse effects.
• Against GABPbeta1L, which enables unlimited growth in GBM cells, 2 treatment approaches are being developed in the laboratory. The first is to design small-molecule inhibitors targeting GABPbeta1L. The other is to develop CRISPR-based treatment, meaning a genetic intervention to prevent production of the GABPBETA1L protein. This study tested the CRISPR approach in mouse models transplanted with human brain cancer cells. Both approaches remain experimental. More analyses are needed before they reach the clinical stage. Testing the approach in other tumor models is also being considered.
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