Annual Report 2023

Division of Collaborative Research and Development

Akihiro Ohashi, Toru Kiyono, Takehiro Nakao, Tomoko Yamamori, Ryo Kamata, Chiaki Mashima, Hitoshi Saito, Emi Ito, Yasushi Kawagishi, Misato Kamini, Hiroki Yamashita, Takuya Nakatsuru, Keita Hirouchi, Yukie Kashima

Introduction

 Integrating knowledge from basic and clinical research, our laboratory conducts drug discovery projects targeting novel cancer therapeutics. As drug discovery targets, we particularly focus on “chromosomal instability (CIN),” one of the hallmarks of cancer, using diverse research approaches such as chemical biology, molecular and cellular biology, and multi-omics analysis. In addition, we have established research assets for single-cell RNA sequencing (scRNA-seq) and spatial analysis in clinical specimens, which allow us to conduct temporal and spatial analysis of “genomic instability of cancer cells” in tumor microenvironment (TME). We also promote collaborative research with overseas research institutions and biotech companies: e.g. AI-driven drug discovery project with the Frederick National Laboratory for Cancer Institute (FNL) in the United States or an oxidative stress inducer project with Arjuna Therapeutics in Spain.

Research Activities

 We have published preclinical pharmacological data of the CDC7 inhibitor project, which has been our focus project for the past several years (Morita TY. et al., Nat. Commun. 2023). In this paper, we show that CDC7 inhibitors induce DNA replication stress-mediated antitumor immunity, enhancing antitumor effects of immune checkpoint inhibitors in preclinical models. These findings propose a novel molecular mechanism for CDC7 inhibitors on antitumor immunity. In TME research platform, research protocols for scRNA-seq and spatial analysis were established in clinical specimens. In the collaboration projects with FNL and Arjuna, pharmacological and mechanistic analyses are being conducted as planned. These results were presented at international conferences such as EORTC-NCI-AACR conference. Other collaboration projects are also progressing on schedule.

Education

 The division head was seconded to Astellas Pharma Immuno-Oncology division with tenure to experience business processes for drug discovery projects. We educated a physician scientist from the Department of Medical Oncology about basic and TR research with chemical biology and molecular biology methods. We also accepted two external MD Ph.D. students (Jikei Medical University and Hokkaido University) as visiting researchers to provide guidance on basic and TR research.

Future Prospects

 Using cutting-edge technologies, we will elucidate the molecular mechanisms of chromosomal instability and drug resistance in TME. Based on these latest findings, we will promote research and development aiming novel cancer therapeutics in collaboration with academia, biotech, and pharmaceutical companies in Japan and overseas.

List of papers published in 2023

Journal

1. Morita TY, Yu J, Kashima Y, Kamata R, Yamamoto G, Minamide T, Mashima C, Yoshiya M, Sakae Y, Yamauchi T, Hakozaki Y, Kageyama SI, Nakamura A, Lightcap E, Tanaka K, Niu H, Kannan K, Ohashi A. CDC7 inhibition induces replication stress-mediated aneuploid cells with an inflammatory phenotype sensitizing tumors to immune checkpoint blockade. Nature communications, 14:7490, 2023

2. Nakai K, Lin H, Yamano S, Tanaka S, Kitamoto S, Saitoh H, Sakuma K, Kurauchi J, Akter E, Konno M, Ishibashi K, Kamata R, Ohashi A, Koseki J, Takahashi H, Yokoyama H, Shiraki Y, Enomoto A, Abe S, Hayakawa Y, Ushiku T, Mutoh M, Fujita Y, Kon S. Wnt activation disturbs cell competition and causes diffuse invasion of transformed cells through NF-κB-MMP21 pathway. Nature communications, 14:7048, 2023