Annual Report 2020
Department of Pharmacology and Therapeutics
Akinobu Hamada, Tomomi Yoshino, Shoraku Ryu, Mayu Ohuchi, Hitomi Jyo
Introduction
We are focused on the development of pharmacokinetics/pharmacodynamics/Pharmacogenetics (PK/PD/PGx) analyzing systems to evaluate efficacy and toxicity in patients and animal models undergoing chemotherapy. The system provides drug exposure in blood and tissues by using high-sensitivity liquid chromatography tandem mass spectrometry (LC-MS/MS), a spatial drug distribution on tissue using mass spectrometry imaging without labeling reagents, and next generation sequencer systems. The National Cancer Center (NCC), National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), and LSI Medience Corporation (LSIM) started the Japanese Cancer Patient-derived Xenograft (J-PDX) Repository Establishment Program supported by the Japan Agency for Medical Research and Development (AMED) on March 7, 2018.
The Team and What We Do
Our laboratory aims for implementing anticancer drug discovery and development in Japan. In this regard, we are working on “Clinical pharmacological research at a molecular level” using next-generation PK/PD/PGx analyses, novel Molecular Drug Imaging system, and the J-PDX library.
Research activities
1) PK/PD/PGx Project
In recent years, anticancer drug development has shifted from conventional cytotoxic agents to molecular target drugs, antibody-drug conjugate (ADC), and immune-checkpoint inhibitors. Our laboratory established next-generation PK/PD/PGx analyses to achieve precision medicine of antibody drugs. Our novel analyses include precise PK/PD analyses of antibody drugs, immune monitoring system, molecular drug imaging system, and the originally developed NGS PGx panel. Moreover, by collaborating clinicians and clinical pharmacologists, we are working on the translational research of drug discovery and development.
2) Molecular Drug Imaging Project
Molecular imaging is the medical practice and laboratory science of visualizing a molecular process in the living body. Our laboratory has focused on the molecular process of anticancer drugs and corresponding various factors. We have already developed Liquid Chromatography/Mass Spectrometry (LC-MS/MS) imaging system (MSI). By using MSI, we have published many reports about spatial drug distribution, intra-tumoral drug concentration, and intra-tumoral drug heterogeneity. We are also attempting drug concentration analysis at the cell level. In cooperation with KONIKA-MINOLTA, we employed newly developed fluorescent nano-particle (PID). Using the PID method, we expect to clarify the precise mode of action in antibody drugs.
3) J-PDX Project
In the course of drug development, a pre-clinical screening model is the key to success in development. The National Cancer Center (NCC), National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), and LSI Medience Corporation (LSIM) started the Japanese Cancer Patient-derived Xenograft (J-PDX) Repository Establishment Program supported by the Japan Agency for Medical Research and Development (AMED) on March 7, 2018.
The objective of this program is to create an international-level research repository of Japanese Patient-Derived Xenografts (J-PDX) for use in the pharmaceutical industry in addition to nurturing expert personnel to promote academia-industry collaboration in their relevant fields.
Following the requests of the Pharmaceuticals and Medical Devices Agency (PMDA), we are planning to 1) refine bio-ethical rules for the industrial use of J-PDXs, 2) establish a world-class J-PDX repository that includes major cancers (lung, colon, breast, stomach, and uterus) in addition to prostate, pancreatic and rare cancers, along with the associated donors’ clinical information, 3) set criteria for the establishment and use of the J-PDX repository, 4) create standard operating procedures for the storage and use of J-PDXs in GLP-compliant, non-clinical studies, and 5) establish a research platform for fundamental and applied PDX science.
Education
Dr. Hamada is a Visiting Professor, Department of Medical Oncology and Translational Research, Graduate School of Medical Sciences, Kumamoto University.
Future Prospects
The combination of PK/PD/PGx analyses, molecular drug imaging technique, and establishment of J-PDX library will provide us with more accurate information about anticancer drugs. These systems will enable us to establish exceptional drug discovery infrastructure in Japan and establish personalized medicine in the future.
List of papers published in 2020
Journal
1. Nakamura IT, Ikegami M, Hasegawa N, Hayashi T, Ueno T, Kawazu M, Yagishita S, Goto Y, Shinno Y, Kojima Y, Takamochi K, Takahashi F, Takahashi K, Mano H, Kohsaka S. Development of an optimal protocol for molecular profiling of tumor cells in pleural effusions at single-cell level. Cancer Sci, 112:2006-2019, 2021
2. Shirasawa M, Yoshida T, Takayanagi D, Shiraishi K, Yagishita S, Sekine K, Kanda S, Matsumoto Y, Masuda K, Shinno Y, Okuma Y, Goto Y, Horinouchi H, Hamada A, Kohno T, Yamamoto N, Watanabe SI, Ohe Y, Motoi N. Activity and Immune Correlates of Programmed Death-1 Blockade Therapy in Patients With Advanced Large Cell Neuroendocrine Carcinoma. Clin Lung Cancer, 2021
3. Yagishita S, Kato K, Takahashi M, Imai T, Yatabe Y, Kuwata T, Suzuki M, Ochiai A, Ohtsu A, Shimada K, Nishida T, Hamada A, Mano H. Characterization of the large-scale Japanese patient-derived xenograft (J-PDX) library. Cancer Sci, 112:2454-2466, 2021
4. Matsuda K, Kobayakawa T, Kariya R, Tsuchiya K, Ryu S, Tsuji K, Ishii T, Gatanaga H, Yoshimura K, Okada S, Hamada A, Mitsuya H, Tamamura H, Maeda K. A Therapeutic Strategy to Combat HIV-1 Latently Infected Cells With a Combination of Latency-Reversing Agents Containing DAG-Lactone PKC Activators. Front Microbiol, 12:636276, 2021
5. Noda K, Matsuda K, Yagishita S, Maeda K, Akiyama Y, Terada-Hirashima J, Matsushita H, Iwata S, Yamashita K, Atarashi Y, Watanabe S, Ide N, Yoshida T, Ohmagari N, Mitsuya H, Hamada A. A novel highly quantitative and reproducible assay for the detection of anti-SARS-CoV-2 IgG and IgM antibodies. Sci Rep, 11:5198, 2021
6. Tsubata Y, Shinomiya S, Inoue K, Ishikawa N, Saito R, Nakashima K, Hotta K, Hamada A, Nagashima F, Ando Y, Morita S, Kobayashi K, Isobe T. Protocol for a multi-site, cluster-randomized, phase III, comparative clinical trial of geriatric assessment of older patients with non-small-cell lung cancer: the ENSURE-GA study. BMC Geriatr, 21:74, 2021
7. Ohuchi M, Yagishita S, Taguchi K, Goto Y, Fukahori M, Enoki Y, Shimada T, Yamaguchi M, Matsumoto K, Hamada A. Use of an alternative signature peptide during development of a LC-MS/MS assay of plasma nivolumab levels applicable for multiple species. J Chromatogr B Analyt Technol Biomed Life Sci, 1162:122489, 2021
8. Hirata T, Ozaki S, Tabata M, Iwamoto T, Hinotsu S, Hamada A, Motoki T, Nogami T, Shien T, Taira N, Matsuoka J, Doihara H. A Multicenter Study of Docetaxel at a Dose of 100 mg/m(2) in Japanese Patients with Advanced or Recurrent Breast Cancer. Intern Med, 60:1183-1190, 2021
9. Otani S, Sasaki J, Nakahara Y, Fukui T, Igawa S, Naoki K, Bessho A, Hosokawa S, Fukamatsu N, Nakamura Y, Kasai T, Sugiyama T, Tokito T, Seki N, Hamada A, Okamoto H, Masuda N. Phase II study of amrubicin plus erlotinib in previously treated, advanced non-small cell lung cancer with wild-type epidermal growth factor receptor (TORG1320). Invest New Drugs, 39:530-536, 2021
10. Arakawa S, Yoshida T, Shirasawa M, Takayanagi D, Yagishita S, Motoi N, Ohe Y. RB1 loss induced small cell lung cancer transformation as acquired resistance to pembrolizumab in an advanced NSCLC patient. Lung Cancer, 151:101-103, 2021
11. Ichikawa A, Fujita Y, Hosaka Y, Kadota T, Ito A, Yagishita S, Watanabe N, Fujimoto S, Kawamoto H, Saito N, Yoshida M, Hashimoto M, Minagawa S, Hara H, Motoi N, Yamamoto Y, Ochiya T, Araya J, Kuwano K. Chaperone-mediated autophagy receptor modulates tumor growth and chemoresistance in non-small cell lung cancer. Cancer Sci, 111:4154-4165, 2020
12. Ryu S, Ohuchi M, Yagishita S, Shimoi T, Yonemori K, Tamura K, Fujiwara Y, Hamada A. Visualization of the distribution of nanoparticle-formulated AZD2811 in mouse tumor model using matrix-assisted laser desorption ionization mass spectrometry imaging. Sci Rep, 10:15535, 2020
13. Nosaki K, Yamanaka T, Hamada A, Shiraishi Y, Harada T, Himeji D, Kitazaki T, Ebi N, Shimose T, Seto T, Takenoyama M, Sugio K. Erlotinib for Non-Small Cell Lung Cancer with Leptomeningeal Metastases: A Phase II Study (LOGIK1101). Oncologist, 25:e1869-e1878, 2020
14. 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
15. Miyamoto S, Azuma K, Ishii H, Bessho A, Hosokawa S, Fukamatsu N, Kunitoh H, Ishii M, Tanaka H, Aono H, Nakahara Y, Kusaka K, Hosomi Y, Kikuchi N, Mori Y, Itani H, Hamada A, Yamada K, Okamoto H. Low-Dose Erlotinib Treatment in Elderly or Frail Patients With EGFR Mutation-Positive Non-Small Cell Lung Cancer: A Multicenter Phase 2 Trial. JAMA Oncol, 6:e201250, 2020
16. Kawachi A, Yamashita S, Okochi-Takada E, Hirakawa A, Tsuda H, Shimomura A, Kojima Y, Yonemori K, Fujiwara Y, Kinoshita T, Ushijima T, Tamura K. BRCA1 promoter methylation in breast cancer patients is associated with response to olaparib/eribulin combination therapy. Breast Cancer Res Treat, 181:323-329, 2020
17. Mizuno T, Kojima Y, Yonemori K, Yoshida H, Sugiura Y, Ohtake Y, Okuma HS, Nishikawa T, Tanioka M, Sudo K, Shimomura A, Noguchi E, Kato T, Shimoi T, Uno M, Ishikawa M, Fujiwara Y, Ohe Y, Tamura K. HER3 protein expression as a risk factor for post-operative recurrence in patients with early-stage adenocarcinoma and adenosquamous carcinoma of the cervix. Oncol Lett, 20:38, 2020
18. Mizuno T, Kojima Y, Yonemori K, Yoshida H, Sugiura Y, Ohtake Y, Okuma HS, Nishikawa T, Tanioka M, Sudo K, Shimomura A, Noguchi E, Kato T, Shimoi T, Uno M, Ishikawa M, Fujiwara Y, Ohe Y, Tamura K. Neoadjuvant chemotherapy promotes the expression of HER3 in patients with ovarian cancer. Oncol Lett, 20:336, 2020