Annual Report 2019

Team Makinoshima

Hideki Makinoshima, Joji Nakayama, Tomoyuki Miyashita, Takako Okamoto, Ami Maruyama, Megumi Enmi

Introduction

 At the time of carcinogenesis or cancer progression, homeostasis that keeps the state of the living body constant is broken. We hypothesized that metabolites that induce carcinogenesis and the metabolic system unique to cancer cells are overproduced or reduced in the individual, and the metabolites themselves contribute to the development and malignancy of cancer beyond its homeostatic mechanism. We are analyzing cancer cells, tumor tissues and blood samples from the viewpoint of cancer metabolism.

The Team and What We Do

 In fiscal 2019 as well, we aimed to identify metabolites and metabolic pathways peculiar to cancer and to discover new drugs targeting them. In joint research between the Institute for Advanced Biosciences, Keio University and the National Cancer Center, metabolomic analysis of cancer was performed on patient-derived samples and samples collected from cancer cell lines and mouse models. In drug discovery research targeting metabolic pathways characteristic of cancer, we proposed the possibility of a new therapeutic method that inhibits the novel biosynthetic pathway of purine nucleic acid with antifolates and the reuse pathway with a new drug (Figure 1). We elucidated the nucleic acid metabolism control mechanism in small cell lung cancer, analyzed cholesterol metabolites related to breast cancer metastasis, elucidated the control mechanism of nucleic acid biosynthesis in breast cancer, and clarified the mechanism of drug resistance to antifolate antagonists in malignant pleural mesenteric tumors.

Figure 1. Development of a novel therapy inhibiting the nucleic acid reuse pathway

Research activities

 Using small cell lung cancer, where cell proliferation is active, as a research material, we established a cell line in which the gene of the enzyme HPRT1 important for the purine nucleic acid reuse pathway was knocked out, investigated the susceptibility to antifolates, and performed new biosynthesis and re-growth. We examined the possibility of combination therapy using inhibitors of the utilization route (Figure 2). Part of the molecular mechanisms that control cancer cell metastasis and gastrula invasion are shared; screening for compounds that interfere with gastrula invagination in zebrafish embryos was performed and inhibiting of metabolic enzymes involved in cortisol production, which was caused by the HSD11β1 inhibitor adrenosterone, was identified. Treatment of breast cancer cells with this adrenosterone can suppress the motility of breast cancer cells, and even in an experimental system in which human breast cancer cells were transplanted into zebrafish, results in which adrenosterone suppresses metastasis were obtained. These results were published as a paper in an American cancer journal. HPRT1-deficient cells were established in breast cancer and malignant pleural mesothelioma. Furthermore, in malignant pleural mesothelioma, drug-resistant cell lines of antifolates were established.

Figure 2. Antifolate-sensitivity in HPRT1-knocked-out SCLC cells

Education

 Yuki Konno (Keio University Institute for Advanced Biosciences, Special Research Student)

 Yusuke Murase (Hokkaido University Graduate School of Veterinary Medicine, Internship)

Future prospects

 In FY2020, we will proceed with the analysis of HPRT1-deficient cells and antifolate-resistant cells to elucidate the nucleic acid biosynthesis control mechanism. At the same time, we are studying the control mechanism of nucleic acid metabolic pathways using animal models, and we plan to continue to verify it from next year onward. We will publish papers on research results and start joint research with companies in Yamagata Prefecture.