Now in Japan, we are facing the era when one in two people will experience cancer. While more than 370 thousand people die of cancer every year, its age-adjusted mortality rate is decreasing. One reason for this trend is that molecular targeting drugs have significantly improved the treatment outcomes for cancer patients. However, we still have many unsolved problems, including cancer without obvious Achilles’ heel, undruggable target molecules and drug resistance, which hinders complete eradication of the disease. This Laboratory consists of three independent labs, which are investigating mechanisms for telomere maintenance and cancer stemness (Seimiya lab), cellular adaptation to tumor microenvironment (Tomida lab), anticancer drug resistance and cancer metastasis (Katayama lab), respectively. Based on these basic researches, we are also conducting applied and translational researches for new drug development.
Visiting Professor Hiroyuki SEIMIYA【Keyword】Molecular Target, Cancer Drug Discovery, Telomere, G-quadruplex, Cancer Stem Cell
Unusual maintenance of chromosome ends, telomeres, supports infinite cancer cell growth. This system will also support so-called cancer stem cells, which contribute to initiation, metastasis, and recurrence of the disease. We are investigating the molecular mechanisms for telomere maintenance, cell immortality, and cancer stemness. Based on these basic researches, we are also developing innovative druggable seeds. First, we are developing telomere-targeting drugs, such as G-quadruplex (G4) ligands, which stabilize G4s, unusual higher-order nucleic acid structures in the genome, and preferentially attack glioma stem cells and other intractable cancer. Second, we are developing chemical inhibitors for the poly (ADP-ribose) polymerase called tankyrase. This enzyme promotes telomere elongation by telomerase and Wnt/β-catenin signaling in cancer. Third, employing functional genomics and comprehensive gene expression and single-cell analyses, we are pursuing therapeutic molecular targets of cancer stem cells.
Visiting Professor Akihiro TOMIDA【Keyword】Tumor Microenvironment, Drug Discovery, Tumor Metabolism, Unfolded Protein Response, Autophagy
Cancer cells in solid tumors are often surrounded by the stressful microenvironment, such as hypoxia (low oxygen) and low glucose, due to insufficient blood supply. The stressful microenvironment is thought to be a major cause of tumor progression and chemotherapy resistance. However, such stress conditions are not observed in normal tissue, and therefore, can be exploited for selective killing of tumor cells. To identify new molecular targets, we are studying the molecular mechanisms of the cellular adaptive response to microenvironmental stress, by using the genome technologies. Specifically, we are interested in unfolded protein response, hypoxic response, glucose metabolism, autophagy and epigenetic regulation. We are also studying inhibitors of the adaptive response and their mechanisms of action to develop a new class of molecular cancer therapeutics.
Visiting Associate Professor Ryohei KATAYAMA【Keyword】Drug resistance, kinase inhibitor, immune checkpoint inhibitor, cancer metastasis, platelets
One of the goals of our research is to identify the molecular mechanisms of the drug resistance against molecular targeted therapy and immune checkpoint inhibitor in cancer, and find the therapeutic strategies to overcome the resistance. To achieve the goal, we examine the resistant mechanisms using the clinical specimens from the cancer patients relapsed on those drug treatments by collaborating with the physicians in our cancer institute hospital in JFCR, under approved IRB. We also focusing on the mechanisms of cancer metastasis (the spread of cancer cells from the primary tumor organ to surrounding tissues or distant organs), which is the primary cause of cancer morbidity and mortality. We previously identified that Aggrus/Podoplanin overexpression in cancer cells induce platelet aggregation thar resulting in the formation of pulmonary metastasis. Thus, we are now developing anti-Podoplanin targeted monoclonal antibody and inhibitors.
