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Epigenomics
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Introduction
Cancer diagnosis, prevention, and therapy taking advantage of epigenomics
Cancer diagnosis, prevention, and therapy taking advantage of epigenomics
Epigenetic mechanisms can change gene function without alterations in DNA sequences and are deeply involved in cancer development. We apply genome-wide epigenetic information (epigenome) to cancer diagnosis, prevention, and therapy.
Cancer diagnosis
- The epigenetic field for cancerization and its application to cancer risk diagnosis: Aberrant DNA methylation, a major mechanism of epigenetic alterations, is induced by chronic inflammation triggered by Helicobacter pylori (H. pylori) infection. We demonstrated that aberrant DNA methylation was accumulated in normal-appearing tissues before cancer developed. Our multicenter prospective cohort study demonstrated that the assessment of the alterations can be used to predict cancer risk. We are also conducting another multicenter prospective study involving 1,800 healthy people after H. pylori eradication to apply epigenome cancer risk diagnosis to this population, which exceeds ten million in Japan.
- Epigenetic markers to predict therapeutic responses: Using cutting-edge epigenome technologies, we identified an epigenetic marker that can predict a complete response before surgery in HER2-positive breast cancer patients. We are now investigating the molecular mechanisms of why this marker can predict a complete response and how it is involved in the response.
Cancer prevention
- The mechanism of the induction of aberrant DNA methylation by chronic inflammation and its application to cancer prevention: The induction of epigenetic alterations is now regarded as one of the most important mechanisms of the development of inflammation-associated cancer. We identified the mechanisms of how H. pylori infection induced aberrant DNA methylation and showed that suppression of aberrant DNA methylation was a useful strategy for cancer prevention in animal models. Now, we are exploring a strategy targeting aberrant DNA methylation for cancer prevention.
Cancer therapy
- The development of epigenetic therapy: The strategy of removing aberrant epigenetic alterations is now used in practice for hematological malignancies and is being developed for solid tumors. We showed that DNA demethylating agents can enhance the effects of anticancer agents and differentiating agents. We also developed novel prodrugs of a DNA demethylating agent that exhibited greater stability and less toxicity, in collaboration with a pharmaceutical company. Furthermore, we showed the importance of targeting aberrant epigenetic alterations in cancer stroma and proposed a novel strategy that can normalize cells in a cancer ecosystem.
- The development of drugs based on DNA methylation synthetic lethality: Cancer therapy based on synthetic lethality is believed to have few adverse effects because it targets only cancer cells, not normal cells. Knowing that DNA methylation is a critical mechanism for gene silencing like gene mutations, we are searching for genes that can be a partner of synthetic lethality with a methylation-silenced gene.