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Research Webzine of the KAIST College of Engineering since 2014

Spring 2025 Vol. 24

Health

A novel therapeutic strategy for cancer that combines IT and BT

July 27, 2023 hit 83

A novel therapeutic strategy for cancer that combines IT and BT

Prof. Kwang-Hyun Cho’s Laboratory for Systems Biology and Bio-Inspired Engineering (http://sbie.kaist.ac.kr) in the Department of Bio and Brain Engineering has developed a novel systems biological approach to find an optimal combinatorial treatment by combining mathematical modeling, large-scale computer simulation, and biological experimentation.

Article | Spring 2014

Cellular signaling pathways are highly interconnected to form a complex network that regulates cell fate determination in a delicate way. They are key targets of therapeutic strategies, like those aimed at killing cancer cells. However, agents that cause DNA damage in cancer cells lead to cell death through a complicated network of pathways, including positive and negative feedback loops, which control the activity of the tumor suppressor p53.

To help clarify more effective strategies to promote cell death in cancer cells, Prof. Kwang-Hyun Cho’s lab used a systems biological approach that combines IT and BT. In his approach, the potential energy landscape of the complex human signaling network was constructed using a large-scale computer simulation as a three-dimensional surface in which depressions represent stable states or “attractors”. These attractors represent alternative cell fates.

With a simplified p53 regulatory network analyzed with a Boolean network model, Prof. Kwang-Hyun Cho’s result revealed that key network components, which determine both p53 dynamics and the cell fate outcome in response to DNA damage, are feedbacks and interactions between p53, Mdm2, Wip1, Cyclin G, and ATM. Disruption of the above critical feedback controls was found to not only result in a change of p53 dynamics but also the alteration of cell fate outcomes.

An attractor landscape analysis was then employed to investigate the DNA damage response of a representative breast cancer cell line, MCF7, and the effect of nutlin-3, a well-known inhibitor of Mdm2, in comparison with normal cells. The treatment of nutlin-3 in combination with the inhibition of Wip1 resulted in a synergistic effect in producing much larger basins of cell death attractors compared to the single treatment of either Wip1 inhibition or nutlin-3.

The predicted synergistic effect was validated by a single-cell imaging experiment, using a fluorescent p53 reporter line of MCF7. The experimental data suggest that a combinatorial treatment of nutlin-3 and Wip1 inhibitor is a more effective strategy for inducing apoptosis in response to DNA-damaging chemotherapeutics.

This study demonstrates that system-level analysis of p53 network dynamics and its regulation using an attractor landscape can be employed to understand the complex cell fate decision mechanism and to identify novel therapeutic strategies for treating cancer.

This study also suggested a possible paradigm shift to “network pathology,” where Prof. Cho explained that we can use network information instead of molecular information for personalized diagnosis of complex disease. The study further suggested the new concept of “computational chemotherapy”, whish can provide an optimal therapeutic strategy for each patient on the basis of network pathology (K. H. Cho. Signaling networks, network pathology and computational chemotherapy. Oncotarget. 2013;4:178-179). This study was published in Science Signaling as a cover paper (http://stke.sciencemag.org/content/vol5/issue251/cover.dtl) and highlighted in the Editor’s Choice of Science as a new promising anti-cancer therapy (http://stke.sciencemag.org/cgi/content/full/sci;338/6110/1010-c). This study is a good example of how IT and BT can be combined to provide an innovative answer to an unresolved problem in life sciences.