Annual Report 2019
Division of Clinical Pharmacology and Translational Research
Akinobu Hamada
Introduction
The Division of Molecular Pharmacology and the Department of Molecular Imaging and Pharmacokinetics focus on the development of pharmacokinetics/pharmacodynamics/pharmacogenetics (PK/PD/PGx) analysis systems to evaluate efficacy and toxicity in patients and animal models treated with 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 by using mass spectrometry imaging without labeling reagents, and next-generation sequencer systems. The National Cancer Center (NCC), the 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 to implement anticancer drug discovery and development in Japan. In this regard, we are working on “Clinical pharmacological research at a molecular level” by 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 conjugates (ADCs), and immune-checkpoint inhibitors. Our laboratory established next-generation PK/PD/PGx analyses to achieve Precision Medicine for antibody drugs. Our novel analyses include precise PK/PD analyses of antibody drugs, immune monitoring systems, molecular drug imaging systems, and originally developed NGS PGx panels. Moreover, by collaborating with clinicians and clinical pharmacologists, we are working on 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 a living body. Our laboratory focused on the molecular process of anticancer drugs and various corresponding factors. We had already developed a Liquid Chromatography / Mass Spectrometry (LC-MS/MS) imaging system (MSI). By using MSI, we published many reports about spatial drug distribution, intra-tumoral drug concentration, and intra-tumoral drug heterogeneity. Moreover, we are also undertaking drug concentration analysis at the cell level. In cooperation with KONIKA-MINOLTA, we employed newly developed fluorescent nano-particles (PID). Using the PID method, we expect to clarify the precise modes 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. The National Cancer Center (NCC), the 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-PDXs) 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, 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 at the 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 techniques, and the establishment of the J-PDX library will provide us with more accurate information about anticancer drugs. These systems will enable us to establish an exceptional drug discovery infrastructure in Japan and establish personalized medicine in the future.
List of papers published in 2019
Journal
1. Shinno Y, Goto Y, Ohuchi M, Hamada A, Nokihara H, Fujiwara Y, Ohe Y. The long half-life of programmed cell death protein 1 inhibitors may increase the frequency of immune-related adverse events after subsequent EGFR tyrosine kinase inhibitor therapy. JTO Clinical and Research Reports, 1:1-6, 2020
2. Takahashi M, Miki S, Fujimoto K, Fukuoka K, Matsushita Y, Maida Y, Yasukawa M, Hayashi M, Shinkyo R, Kikuchi K, Mukasa A, Nishikawa R, Tamura K, Narita Y, Hamada A, Masutomi K, Ichimura K. Eribulin penetrates brain tumor tissue and prolongs survival of mice harboring intracerebral glioblastoma xenografts. Cancer Sci, 110:2247-2257, 2019
3. Yagishita S, Hamada A. Monoclonal antibody pharmacogenomics in cancer treatment. J Cancer Metastasis Treat, 5:75, 2019
4. Osawa T, Shimamura T, Saito K, Hasegawa Y, Ishii N, Nishida M, Ando R, Kondo A, Anwar M, Tsuchida R, Hino S, Sakamoto A, Igarashi K, Saitoh K, Kato K, Endo K, Yamano S, Kanki Y, Matsumura Y, Minami T, Tanaka T, Anai M, Wada Y, Wanibuchi H, Hayashi M, Hamada A, Yoshida M, Yachida S, Nakao M, Sakai J, Aburatani H, Shibuya M, Hanada K, Miyano S, Soga T, Kodama T. Phosphoethanolamine Accumulation Protects Cancer Cells under Glutamine Starvation through Downregulation of PCYT2. Cell Rep, 29:89-103.e7, 2019
5. Endo-Tsukude C, Kato M, Kaneko A, Iida S, Kuramoto S, Ishigai M, Hamada A. Risk of CYP2C9 induction analyzed by a relative factor approach with human hepatocytes. Drug Metab Pharmacokinet, 34:325-333, 2019
6. Iwamoto N, Takanashi M, Shimada T, Sasaki J, Hamada A. Comparison of Bevacizumab Quantification Results in Plasma of Non-small Cell Lung Cancer Patients Using Bioanalytical Techniques Between LC-MS/MS, ELISA, and Microfluidic-based Immunoassay. AAPS J, 21:101, 2019
7. Shimomura A, Yonemori K, Yoshida M, Yoshida T, Yasojima H, Masuda N, Aogi K, Takahashi M, Naito Y, Shimizu S, Nakamura R, Hamada A, Michimae H, Hashimoto J, Yamamoto H, Kawachi A, Shimizu C, Fujiwara Y, Tamura K. Gene Alterations in Triple-Negative Breast Cancer Patients in a Phase I/II Study of Eribulin and Olaparib Combination Therapy. Transl Oncol, 12:1386-1394, 2019
8. Nishidate M, Hayashi M, Aikawa H, Tanaka K, Nakada N, Miura SI, Ryu S, Higashi T, Ikarashi Y, Fujiwara Y, Hamada A. Applications of MALDI mass spectrometry imaging for pharmacokinetic studies during drug development. Drug Metab Pharmacokinet, 34:209-216, 2019
9. Yonemori K, Shimomura A, Yasojima H, Masuda N, Aogi K, Takahashi M, Naito Y, Shimizu S, Nakamura R, Hashimoto J, Yamamoto H, Hirakawa A, Michimae H, Hamada A, Yoshida T, Sukigara T, Tamura K, Fujiwara Y. A phase I/II trial of olaparib tablet in combination with eribulin in Japanese patients with advanced or metastatic triple-negative breast cancer previously treated with anthracyclines and taxanes. Eur J Cancer, 109:84-91, 2019