Antitumor Response of Left-handed Z-DNA Reinvigorates Immunotherapy’s Efficacy

Facing the problem of ineffectiveness of immunotherapy due to tumor resistance, a study published in Nature recently proposed a novel small molecule drug, curaxin CBL0137, that induces tumor necrosis by inducing the synthesis of Z-DNA in organisms. This drug not only exhibits a high degree of immunogenicity, but the team also demonstrated that Z-DNA can counteract the drug resistance mechanism developed by melanoma cells and restore the efficacy of immune checkpoint inhibitors. 

Immune checkpoint inhibitors are a major breakthrough in cancer therapy in recent years. The action mechanism is to inhibit immune checkpoint actions of cancer cells so that the immune system can accurately identify tumor antigens and launch attacks. For some patients who have failed to respond to conventional cancer therapies, this immunotherapy offers new treatment opportunities, but maintaining the long-term effects of immune checkpoint inhibitors and improving response rates to treatment are currently a major challenge.

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What is the Relationship Between Z-DNA and Antitumor Immune Response?

In general, DNA can be categorized into A-, B-, and Z-DNA according to their structural differences, while A-DNA and B-DNA are right-handed structures and Z-DNA is a less common left-handed structure. Z-DNA is formed in normal cells by sequences called flipons, that can reversibly flip the molecule to a left-handed conformation under physiological conditions. Scientists suggest that the flipon phenomenon in Z-DNA in contrast to common DNA constructs, may be an evolutionary strategy for lower mutation rate during the course of biological evolution.

One of the important roles of Z-DNA is to regulate the immune response of organisms against foreign viruses or infected cells. The two key proteins involved in this immune mechanism are ADAR1 and ZBP1; both proteins have Zα-binding domains in their structures and show high affinity for Z-DNA. 

In case of an inflammatory response, high concentrations of interferon induce the action of ADAR1 and ZBP1 on tumor cells, although the two proteins have opposite purposes. When ADAR1 Zα binds to Z-DNA, the immune system is weakened and cancer proliferation relies on highly expressed ADAR1 on fibroblast cells to escape from the interception of the immune system. Conversely, the binding of ZBP1 Zα to Z-DNA activates the immune action and triggers tumor cell death.

The new small molecule drug proposed in this study induces Z-DNA synthesis, and its anticancer effect is achieved by activating ZBP1 to disrupt fibroblast growth and bypass ADAR1, which supports cancer cell proliferation, to trigger tumor cell death.

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Being Highly Immunogenic, the Drug is Effective Even Against Cancer Mutations

This experimental small molecule drug, CBL0137, is a member of the curaxin family of breast cancer drugs and is highly immunogenic, thus producing efficacy even when cancer cells have increased cumulative mutations. In a mouse model of melanoma that is ineffective to immunotherapy, CBL0137 has been shown to restore the function of the target PD-1 immune checkpoint inhibitor by generating Z-DNA to induce tumor cell necrosis.

While the current study shows no safety concerns for CBL0137, more trials are needed to evaluate its efficacy in combination with anti-PD-1 immunotherapy. A phase I clinical trial of CBL0137 is expected to begin in the second half of this year in melanoma patients treated with immunotherapy.

Dr. Siddharth Balachandran from Fox Chase Cancer Center in Philadelphia is one of the co-authors of the study. He commented that the study is an important one for patients who have failed first-line immunotherapy and that the addition of immune adjuvants to cancer immunotherapy could reinvigorate its efficacy in patients with low response rates to immunotherapy.

Written by Kathy Huang, translated by Richard Chau

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