Annual Report 2020
Division of Translational Genomics (Kashiwa Campus)
Susumu S. Kobayashi, Akihiro Ohashi, Kosuke Tanaka, Tomoko Yamamori, Hibiki Udagawa, Jie Liu, Kei Oguchi, Takuma Hayashida, Yumi Hakozaki, Hiroko Nagayama
Introduction
The Division of Translational Genomics was restructured and the current division started when Susumu Kobayashi was recruited to the NCC in April 2018. We closely collaborate with intramural and extramural clinicians and researchers to develop genome biomarker diagnostics, explore rational molecular targets for anti-cancer therapies, and elucidate the molecular mechanisms of tumorigenesis, progression, and therapeutic responses.
The Team and What We Do
Our dream is to conquer cancer, and we work hard to achieve it. In addition to our weekly laboratory meetings, we have combined weekly meetings with the Division of Translational Informatics. We also participate in center-wide research meetings and invite outside speakers to present the most up-to-date science.
Research activities
For the past decade, molecular-target drugs have been game-changers for cancer therapeutic strategies. In most cases, however, these therapies fail due to intrinsic and acquired drug resistance. Our interests lie in studying the mechanisms of action and resistance mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKIs) in lung cancer using multi-omics analyses, single-cell analyses, and mathematical modeling. In collaboration with pharmaceutical companies, we evaluated several novel EGFR TKIs in lung cancer patients with EGFR exon 20 mutations. We have also started research on genomic instability, one of the cancer hallmarks. We are interested in the mechanisms by which aberrant DNA replication and repair play crucial roles in tumorigenesis. A deep understanding of “Cancer Hallmarks and Vulnerability” is important for discovering the target molecules for novel drug development.
Clinical trials
We have participated in several clinical trials to support the translational aspects of studies.
Education
We have accepted and trained the following trainees: Graduate students from the University of Tokyo and staff physicians and residents of the National Cancer Center Hospital East. We gave a few educational seminar presentations at the University of Tokyo.
Future Prospects
In collaboration with other divisions in the NCC, other institutions, and pharmacological companies, we will investigate the mechanisms of action and resistance to targeted therapies including immune-checkpoint inhibitors. We will also continue to investigate genomic instability in cancers and identify molecules that determine vulnerability. Our major goal is to identify and develop novel therapeutics to treat cancers through our research activities.
List of papers published in 2020
Journal
1. Kashima Y, Togashi Y, Fukuoka S, Kamada T, Irie T, Suzuki A, Nakamura Y, Shitara K, Minamide T, Yoshida T, Taoka N, Kawase T, Wada T, Inaki K, Chihara M, Ebisuno Y, Tsukamoto S, Fujii R, Ohashi A, Suzuki Y, Tsuchihara K, Nishikawa H, Doi T. Potentiality of multiple modalities for single-cell analyses to evaluate the tumor microenvironment in clinical specimens. Sci Rep, 11:341, 2021
2. Watanabe S, Goto Y, Yasuda H, Kohno T, Motoi N, Ohe Y, Nishikawa H, Kobayashi SS, Kuwano K, Togashi Y. HSP90 inhibition overcomes EGFR amplification-induced resistance to third-generation EGFR-TKIs. Thorac Cancer, 12:631-642, 2021
3. Sehgal K, Rangachari D, VanderLaan PA, Kobayashi SS, Costa DB. Clinical Benefit of Tyrosine Kinase Inhibitors in Advanced Lung Cancer with EGFR-G719A and Other Uncommon EGFR Mutations. Oncologist, 26:281-287, 2021
4. Vasconcelos PENS, Kobayashi IS, Kobayashi SS, Costa DB. Preclinical characterization of mobocertinib highlights the putative therapeutic window of this novel EGFR inhibitor to EGFR exon 20 insertion mutations. JTO Clin Res Rep, 2:2021
5. Sakamoto Y, Xu L, Seki M, Yokoyama TT, Kasahara M, Kashima Y, Ohashi A, Shimada Y, Motoi N, Tsuchihara K, Kobayashi SS, Kohno T, Shiraishi Y, Suzuki A, Suzuki Y. Long-read sequencing for non-small-cell lung cancer genomes. Genome Res, 30:1243-1257, 2020
6. Tsumura R, Koga Y, Hamada A, Kuwata T, Sasaki H, Doi T, Aikawa K, Ohashi A, Katano I, Ikarashi Y, Ito M, Ochiai A. Report of the use of patient-derived xenograft models in the development of anticancer drugs in Japan. Cancer Sci, 111:3386-3394, 2020
7. Fujimoto Y, Morita TY, Ohashi A, Haeno H, Hakozaki Y, Fujii M, Kashima Y, Kobayashi SS, Mukohara T. Combination treatment with a PI3K/Akt/mTOR pathway inhibitor overcomes resistance to anti-HER2 therapy in PIK3CA-mutant HER2-positive breast cancer cells. Sci Rep, 10:21762, 2020
8. Maruyama T, Sasaki A, Iijima S, Ayukawa S, Goda N, Tazuru K, Hashimoto N, Hayashi T, Kozawa K, Sato N, Ishikawa S, Morita T, Fujita Y. ZAK Inhibitor PLX4720 Promotes Extrusion of Transformed Cells via Cell Competition. iScience, 23:101327, 2020
9. Takei H, Fukuda H, Pan G, Yamazaki H, Matsumoto T, Kazuma Y, Fujii M, Nakayama S, Kobayashi IS, Shindo K, Yamashita R, Shirakawa K, Takaori-Kondo A, Kobayashi SS. Alternative splicing of APOBEC3D generates functional diversity and its role as a DNA mutator. Int J Hematol, 112:395-408, 2020
10. Piper-Vallillo AJ, Halbert BT, Rangachari D, Kobayashi SS, Costa DB. Acquired Resistance to Osimertinib Plus Savolitinib Is Mediated by MET-D1228 and MET-Y1230 Mutations in EGFR-Mutated MET-Amplified Lung Cancer. JTO Clin Res Rep, 1:100071, 2020