Annual Report 2018
Division of Molecular Pharmacology / Department of Pharmacology and Therapeutics
Akinobu Hamada, Mituhiro Hayashi, Shigehiro Yagishita, Tomomi Yoshino, Mikiko Suzuki, Shoraku Ryu, Mayu Ohuchi
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) analyzing 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 highsensitivity 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. Recently, the National Cancer Center (NCC), National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), and LSI Medience Corporation (LSIM) started 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, a novel Molecular Drug Imaging System, and 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 (ADC) and immune-checkpoint inhibitors. Our laboratory established next-generation PK/PD/ PGx analyses to realize 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 for 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 a molecular process of anticancer drugs and corresponding various factors. We have 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 developing with drug concentration analysis at the cell level. In cooperation with KONICA-MINOLTA, we employed newly developed fluorescent nanoparticles (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 preclinical 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 worldclass 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 the 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 techniques, and establishment of 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 2018
Journal
1. Mizugaki H, Hamada A, Shibata T, Hosoda F, Nakamura H, Okuma Y, Shukuya T, Umemura S, Horiike A, Fukui T, Kogure Y, Daga H, Urata Y, Yamada K, Saeki S, Fujisaka Y, Nakamura Y, Sato M, Yoshida T, Hotta T, Oizumi S, Fujiwara Y, Ohe Y, Fujiwara Y. Exploration of germline variants responsible for adverse events of crizotinib in anaplastic lymphoma kinase-positive non-small cell lung cancer by target-gene panel sequencing. Lung Cancer, 128:20-25, 2019
2. Okimoto T, Tsubata Y, Hotta T, Hamaguchi M, Nakao M, Hamaguchi SI, Hamada A, Isobe T. A Low Crizotinib Concentration in the Cerebrospinal Fluid Causes Ineffective Treatment of Anaplastic Lymphoma Kinase-positive Non-small Cell Lung Cancer with Carcinomatous Meningitis. Intern Med, 58:703-705, 2019
3. 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
4. Komura M, Yagishita S, Nakamura K, Arano N, Takeshige T, Muraki K, Nagashima O, Izumi H, Tomita S, Sasaki S, Takahashi K. A Case of a Pregnant Woman Diagnosed as Having ALK-rearranged Lung Adenocarcinoma. In Vivo, 32:1205-1209, 2018
5. Kanemaru R, Takahashi F, Kato M, Mitsuishi Y, Tajima K, Ihara H, Hidayat M, Wirawan A, Koinuma Y, Hayakawa D, Yagishita S, Ko R, Sato T, Harada N, Kodama Y, Nurwidya F, Sasaki S, Niwa SI, Takahashi K. Dasatinib Suppresses TGFbeta-Mediated Epithelial-Mesenchymal Transition in Alveolar Epithelial Cells and Inhibits Pulmonary Fibrosis. Lung, 196:531-541, 2018
6. Shimoi T, Hamada A, Yamagishi M, Hirai M, Yoshida M, Nishikawa T, Sudo K, Shimomura A, Noguchi E, Yunokawa M, Yonemori K, Shimizu C, Kinoshita T, Fukuda T, Fujiwara Y, Tamura K. PIK3CA mutation profiling in patients with breast cancer, using a highly sensitive detection system. Cancer Sci, 109:2558-2566, 2018
7. Nishimura M, Hayashi M, Mizutani Y, Takenaka K, Imamura Y, Chayahara N, Toyoda M, Kiyota N, Mukohara T, Aikawa H, Fujiwara Y, Hamada A, Minami H. Distribution of erlotinib in rash and normal skin in cancer patients receiving erlotinib visualized by matrix assisted laser desorption/ionization mass spectrometry imaging. Oncotarget, 9:18540-18547, 2018