Message from the Chief

Update : 2020-07-31

Chief	Hiroyuki Seimiya, Ph.D.The goals of our laboratory are to molecularly pinpoint Achilles’ heels of cancer cells and develop innovative anticancer medicines. At the starting point, we have focused on telomeres, the end-capping structures of chromosomes, which are unusually maintained in most cancer cells for their immortality. We have been developing anticancer small molecules that selectively modulate the behaviors of telomere-related factors (reviewed in Seimiya, Cancer Sci, 2020). The targets include tankyrase poly(ADP-ribose) polymerase, quadruplex structures of guanine-rich nucleic acids (G-quadruplexes), and maintenance factors of cancer stem cells. We are also pursuing the proof-of-concept, resistance mechanisms, and predictive biomarkers of those drug efficacies for the prospective cancer precision medicine.

Telomeres, telomerase and G-quadruplex nucleic acids
Dividing cells in our bodies are gradually losing the tips of chromosomes, called telomeres. Telomere erosion is a timing device for senescence (cellular aging), which prevents emergence of immortalized cells. Most cancer cells show an infinite replicative capacity because they can re-build telomeres by means of activation of an intracellular enzyme, called telomerase, or a recombination-based mechanism called ALT (alternative lengthening of telomeres). We have developed various telomerase inhibitors that shorten telomeres and block unlimited growth of human cancer cells. Meanwhile, the telomeric TTAGGG repeats can form a higher-order nucleic acid structure called G-quadruplex (G4). G4s are widely distributed through the whole genome, especially, at promoters and untranslated regions of cancer-related genes. We are developing chemical compounds called G4 ligands, which stabilize G4s and induce replication stress, DNA damage and rapid cancer cell death.

Tankyrases, the poly(ADP-ribose) polymerases for Wnt signaling
Poly(ADP-ribosyl)ation is one of the most drastic post-translational modifications of proteins. This biochemical reaction is catalyzed by members of the poly(ADP-ribose) polymerase (PARP) family. We have focused on tankyrases (tankyrase-1 and 2), which have been originally identified as PARP members that enhance telomere elongation by telomerase. We have reported that tankyrase inhibition enhances telomere shortening by a telomerase inhibitor and results in earlier crisis of human cancer cells. Intriguingly, tankyrase also works as a positive regulator of Wnt/β-catenin signaling. Tankyrase poly(ADP-ribosyl)ates Axin, a negative regulator of β-catenin, and facilitates nuclear accumulation of β-catenin. We have developed potent and specific tankyrase inhibitors, such as RK-287107 and RK-582, which downregulate β-catenin and inhibit in vivo tumor growth of colorectal cancer cells. These results suggest that tankyrase inhibitors are promising drug seeds for targeting Wnt-driven cancers.

Tumor heterogeneity and cancer stem cells
Accumulating evidence indicates that tumor heterogeneity and plasticity cause resistance to anticancer drugs and relapse of the diseases. Cancer stem cells are subpopulations that retain the abilities to self-renew, initiate tumor formation in vivo, metastasize and resist against radiation and chemotherapy. Employing functional genomics and chemical screenings, we have identified genes that contribute to cancer stemness and chemical compounds that preferentially target cancer stem cells. For example, we found that G4 ligands, such as telomestatin and its synthetic derivatives, induce replicative stress and DNA damage response in CD133-positive glioma stem cells. Furthermore, we found that tankyrase inhibitors repress c-KIT tyrosine kinase gene expression and inhibit the growth of CD44-positive colorectal cancer stem cells. We are also performing single-cell analysis of gastric cancer patient-derived cells and characterizing the anticancer drug-tolerant persister cells.

Chief Hiroyuki Seimiya, Ph.D.

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