An international group of scientists have unlocked a new way to kill hard-to-treat cancers. These tumors resist current immunotherapies, including those using Nobel Prize winning check-point blocking antibodies.
The approach exploits Z-DNA. Rather than twisting to the right like Watson and Crick B-DNA, Z-DNA has a left-handed twist. One role for Z-DNA is to regulate the immune response to viruses. The response involves two proteins that specifically recognize-Z-DNA, AADR1 and ZBP1. They do so through a Zα domain that binds to the Z-DNA structure with high affinity. The Zα domain was originally discovered by Dr. Alan Herbert of InsideOutBio, a communicating author on the paper. The ADAR1 Zα domain turns off the immune response against self, while the other ZBP1 Zα turns on pathways that kill virally infected cells, as previously shown by Dr. Sid Balachandran, the other communicating author on the paper. The interactions between ADAR1 and ZBP1 determine whether a tumor cell lives or dies.
Both Zα proteins are induced to treat during inflammation by interferon. They are not usually present in normal cells. Both proteins are also expressed in tumors, especially in normal cells called fibroblasts that cancer cells force to support their growth. Normally tumors rely on ADAR1 to suppress cell death pathways that would otherwise kill the tumor.
The team found a small molecule that could bypass ADAR1 suppression and directly activated tumor cell death by ZBP1. The drug acts regardless of the mutation that causes the cancer. The form of cell death induced is highly immunogenic. The response destroys the fibroblasts supporting the tumor growth. By doing so, the drug enhances the effectiveness of immunotherapy using the checkpoint blocking antibody targeted at PD-1. The drug is a member of the curaxin family and was introduced to clinic for another reason. The compound has proven safe in Phase I trials but still requires further research to confirm its clinical use in conjunction with anti-PD1 provides a benefit in the treatment of cancers.
Source: This news is originally published by news-medical.net