A team of researchers from Wrocław University of Science and Technology, France, Slovakia, and Taiwan has transformed an initially undesirable property of a clinical-stage anticancer compound, its sensitivity to light, into a potential therapeutic advantage. Upon light activation, the compound induces damage associated with unusual structures in cancer DNA and, in preclinical models, combines strong antitumor activity with activation of an anticancer immune response.  

An article on this topic – “G-quadruplex DNA reprograms the photochemistry of CX-5461 toward radical-driven anticancer activity” – has just been published in Nucleic Acids Research, one of the leading international journals in nucleic acids research.

Its authors are Dr. Marco Deiana, Dr. Marta Dudek (both from the Faculty of Chemistry, WUST), Maria V. Cottini, Dr. Jan Jamroskovic (both from the Slovak Academy of Sciences), Prof. Cyrille Monnereau, Dr. Lhoussain Khrouz (both from ENS de Lyon, France), Dr. Kai-Wei Hsueh, Dr. Yen-Chen Liu, and Dr. Ping-Yen Huang (Senhwa Biosciences, Taiwan), and Jakub Trojnar from the Doctoral School of WUST.

Unconventional Targets in the Fight Against Cancer

Modern oncology is currently seeking methods that enable precise targeting of the replication and transcription mechanisms of cancer cells while minimizing systemic toxicity.  

“One of the most promising avenues of research is the utilization of G-quadruplex (G4) structures. These are unconventional, four-stranded structures that can form in DNA. They are particularly interesting in cancer research because they frequently occur in regulatory regions of genes responsible for tumor growth, cell survival, and genomic stability,” says Dr. Deiana.

In their project, the researchers utilized a compound named CX-5461, which is currently undergoing clinical trials as an anticancer drug. It is one of the first G-quadruplex-binding compounds to be evaluated in such clinical trials.

Turning a Drawback into an Effective Therapy

The starting point for the researchers was the phototoxicity of this compound observed in clinical trials following patients' exposure to sunlight. Rather than treating this property solely as an adverse effect, the scientists decided to turn it into a therapeutic strategy.

“The interaction of CX-5461 with G-quadruplex DNA fundamentally alters its photochemical behavior. Binding to these DNA structures suppresses the generation of singlet oxygen and directs the compound toward radical-driven photochemistry, leading to a significant enhancement of its light-dependent anticancer activity,” explains Dr.  Deiana. “Thus, the DNA structure does not function merely as a passive drug target. It actively dictates how the compound behaves upon light exposure and guides it toward a more efficient anticancer mechanism,” he adds.

From the Laboratory to Animal Models

To verify their hypotheses, a broad spectrum of biophysical, biochemical, and biological model methods was employed, including spectroscopic and photochemical analyses as well as structural DNA studies that allow for the identification of damage sites at single-nucleotide resolution.

Research was conducted on murine colorectal cancer, melanoma, and human melanoma cell lines, while therapeutic efficacy was evaluated in mice bearing syngeneic tumors.

Tumor Destruction and Immune System Mobilization

“In vivo experiments demonstrated significant antitumor activity, while additional analyses indicated the induction of an anticancer immune response. These results suggest that light-activated CX-5461 can not only directly destroy cancer cells but also stimulate the immune system to recognize and attack the tumor,” emphasizes Dr. Deiana.

Furthermore, the therapy induced hallmarks of immunogenic cell death, manifested by surface exposure of calreticulin and the release of HMGB1 protein. Increased infiltration of cytotoxic T lymphocytes (CD8+) into tumors and activation of the interferon signaling pathway were also observed. In one case, long-lasting immunological memory was demonstrated – a mouse in which the tumor completely regressed rejected a re-challenge with cancer cells.

Thus, the study's findings prove that a photogenomic approach based on CX-5461 represents a promising strategy in the fight against cancer. By exploiting the drug's natural affinity for binding to G4 structures alongside its photoreactivity, it is possible to induce precise damage at the very core of cancer cells' genetic machinery.

“Such a solution not only enhances the therapeutic efficacy of a known drug but also engages the patient's immune system to combat the cancer, paving the way for the development of a new class of light-based therapies targeted at genome structure,” notes Dr. Deiana.

Publication Details

G-quadruplex DNA reprograms the photochemistry of CX-5461 toward radical-driven anticancer activity. Jakub Trojnar, Maria V. Cottini, Marta Dudek, Cyrille Monnereau, Lhoussain Khrouz, Kai-Wei Hsueh, Yen-Chen Liu, Ping-Yen Huang, Jan Jamroskovic, Marco Deiana.

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