Annual Report 2019
Division of Translational Genomics (Kashiwa Campus)
Susumu S. Kobayashi, Akihiro Ohashi, Tomoko Yamamori, Masanori Fujii, Yumi Hakozaki, Hiroko Kumakura
Introduction
The new Division of Translational Genomics was restructured and 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 molecular mechanisms of tumorigenesis, progression, and therapeutic responses.
The Team and What We Do
Our dream is to conquer cancers, 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 the 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. We are interested in studying 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. In addition, 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. Deeply understanding “Cancer Hallmarks and Vulnerability” is important to discover the target molecules for novel drug development.
Clinical trials
We have participated in several clinical trials to support 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 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 2019
Journal
1. Udagawa H, Hasako S, Ohashi A, Fujioka R, Hakozaki Y, Shibuya M, Abe N, Komori T, Haruma T, Terasaka M, Fujita R, Hashimoto A, Funabashi K, Yasuda H, Miyadera K, Goto K, Costa DB, Kobayashi SS. TAS6417/CLN-081 Is a Pan-Mutation-Selective EGFR Tyrosine Kinase Inhibitor with a Broad Spectrum of Preclinical Activity against Clinically Relevant EGFR Mutations. Mol Cancer Res, 2019
2. Takei H, Kobayashi SS. Targeting transcription factors in acute myeloid leukemia. Int J Hematol, 109:28-34, 2019
3. Rangachari D, To C, Shpilsky JE, VanderLaan PA, Kobayashi SS, Mushajiang M, Lau CJ, Paweletz CP, Oxnard GR, Janne PA, Costa DB. EGFR-Mutated Lung Cancers Resistant to Osimertinib through EGFR C797S Respond to First-Generation Reversible EGFR Inhibitors but Eventually Acquire EGFR T790M/C797S in Preclinical Models and Clinical Samples. J Thorac Oncol, 2019
4. Radhakrishnan S, Syed R, Takei H, Kobayashi IS, Nakamura E, Sultana F, Kamal A, Tenen DG, Kobayashi SS. Styryl quinazolinones and its ethynyl derivatives induce myeloid differentiation. Bioorg Med Chem Lett, 29:2286-2289, 2019
5. Kashima Y, Suzuki A, Suzuki Y. An Informative Approach to Single-Cell Sequencing Analysis. Adv Exp Med Biol, 1129:81-96, 2019
6. Iwai K, Nambu T, Dairiki R, Ohori M, Yu J, Burke K, Gotou M, Yamamoto Y, Ebara S, Shibata S, Hibino R, Nishizawa S, Miyazaki T, Homma M, Oguro Y, Imada T, Cho N, Uchiyama N, Kogame A, Takeuchi T, Kurasawa O, Yamanaka K, Niu H, Ohashi A. Molecular mechanism and potential target indication of TAK-931, a novel CDC7-selective inhibitor. Sci Adv, 5:eaav3660, 2019
7. Ikemura S, Yasuda H, Matsumoto S, Kamada M, Hamamoto J, Masuzawa K, Kobayashi K, Manabe T, Arai D, Nakachi I, Kawada I, Ishioka K, Nakamura M, Namkoong H, Naoki K, Ono F, Araki M, Kanada R, Ma B, Hayashi Y, Mimaki S, Yoh K, Kobayashi SS, Kohno T, Okuno Y, Goto K, Tsuchihara K, Soejima K. Molecular dynamics simulation-guided drug sensitivity prediction for lung cancer with rare EGFR mutations. Proc Natl Acad Sci U S A, 116:10025-10030, 2019
8. Sehgal K, Peters MLB, VanderLaan PA, Rangachari D, Kobayashi SS, Costa DB. Activity of Brigatinib in the Setting of Alectinib Resistance Mediated by ALK I1171S in ALK-Rearranged Lung Cancer. J Thorac Oncol, 14:e1-e3, 2019
9. Takenaka T, Nakai S, Katayama M, Hirano M, Ueno N, Noguchi K, Takatani-Nakase T, Fujii I, Kobayashi SS, Nakase I. Effects of gefitinib treatment on cellular uptake of extracellular vesicles in EGFR-mutant non-small cell lung cancer cells. Int J Pharm, 572:118762, 2019