Develop new methods for treating refractory tumors From Nature

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In a new study, researchers from the Fox Chase Cancer Center in the United States and the Russian National University of economics reported a new method to kill cancer that is difficult to treat. These tumors resist current immunotherapies, including those that use immune checkpoint blocking antibodies. Relevant research results were published online in the journal Nature on May 25, 2022, with the title of “ADAR1 masks the cancer immunologic promise of zbp1 driven endocroptosis”.

This method utilizes Z-DNA. Z-DNA does not twist to the right like B-DNA, but to the left. One function of Z-DNA is to regulate the immune response to viruses. The immune response involves aadr1 and zbp1, which specifically recognize Z-DNA. They bind to Z-DNA structure with high affinity α The domain does this.

Z α The domain was originally discovered by Dr. Alan Herbert of the Russian State University of higher economics, the co corresponding author of the paper. Z of ADAR1 α The domain turns off the autoimmune response, while the Z α The domain activates the way to kill virus infected cells, as previously discovered by Dr. Sid balachandran of Fox Chase Cancer Center, the co-author of the paper. The interaction between ADAR1 and zbp1 determines whether tumor cells live or die.

Both aadr1 and zbp1 are induced by interferon during inflammation. They usually do not exist in normal cells. Both proteins are also expressed in tumors, especially in normal cells called fibroblasts, where cancer cells force fibroblasts to support their growth. Generally speaking, tumors rely on ADAR1 to inhibit the cell death pathway that kills them.

These authors found a small molecule: cbl0137, which can bypass the inhibition of ADAR1 and directly activate tumor cell death through zbp1. The effect of the drug is not related to the mutation that causes cancer. The cell death form induced by it has high immunogenicity. This effect destroys fibroblasts that support tumor growth. By doing so, the drug enhances the effectiveness of immunotherapy using immune checkpoint blocking antibodies targeting PD-1. The drug is a member of the curaxin family and was introduced into clinical trials for another purpose. The compound has been proved to be safe in phase 1 clinical trials, but further research is still needed to confirm that its clinical use together with anti-pd1 antibody is beneficial to the treatment of cancer.

Z-rna accumulation after ADAR elimination, picture from nature, 2022, doi:10.1038/s41586-022-04753-7.

Dr. Herbert said, “this is the result of a highly collaborative team. It is a milestone in our understanding of how alternative DNA conformations (such as Z-DNA) play an important role in human biology. This paper shows how basic research can lead to new and unexpected treatments. This process took a long time from the initial discovery of Z-DNA α Start with the domain, then go to identify Z that causes human genetic diseases α DNA variants. These findings confirm the biological role of Z-DNA. This new research now enables us to find a new way to treat cancer. This is a happy turning point, because the initial discovery of Z-DNA is widely recognized by the scientific community as having little biological significance, and further research work has not been listed as worthy of funding by the peer review team of the National Institutes of health. “

Z-DNA is formed in normal cells by sequences called flipons, which can be reversibly reversed to the left-handed conformation under physiological conditions. This structure was discovered by accident in the first synthetic crystal analyzed by X-ray crystallography. Other types of flipons also exist and are likely to play an important role in biology. Flipons are highly dynamic structures, which have been difficult to study because it is challenging to determine their exact conformation in cells.

Dr. Herbert said, “this is similar to other highly dynamic systems in physics. You can only find the conformation of flipons by direct measurement, but only if the measurement behavior does not bias the results.”

reference material:

Ting Zhang et al. ADAR1 masks the cancer immunotherapeutic promise of ZBP1-driven necroptosis. Nature, 2022, doi:10.1038/s41586-022-04753-7.

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