Annual Report 2022
Division of Molecular Pharmacology / Department of Pharmacology and Therapeutics
Akinobu Hamada, Shigehiro Yagishita, Tomomi Yoshino, Mikiko Suzuki, Shoraku Ryu, Mayu Ohuchi, Chisato Oto, Ako Takahashi, Chiaki Ushie
Introduction
Clinical pharmacology research is an important step in drug discovery and development research, bridging the gap (so-called “Death Valley”) between non-clinical research and clinical development. In non-clinical studies, pharmacology, safety, and efficacy are investigated using cell lines and experimental animals, followed by Phase I studies in humans. For highly toxic anticancer drugs, clinical pharmacology research, including analysis of the correlation between drug blood concentration (pharmacokinetics, PK) and pharmacodynamic (PD) effects, estimation of concentrations at which efficacy and safety are expected, and identification of drug metabolism or drug transport proteins, has a significant impact on drug discovery and development.
We, the Division of Molecular Pharmacology and the Department of Pharmacology and Therapeutics, are promoting the evaluation of drug distribution in target tissues (tumor local PK), which cannot be done by blood concentration measurement, in addition to the measurement of blood concentration of the target drug in the whole body (systemic PD), which is the central endpoint of conventional PK/PD studies. We are visualizing drug distribution in tumors at the single-cell level using mass spectrometry imaging for small molecule compounds and fluorescence imaging for antibody drugs. We are promoting the application of these techniques for dose optimization, evaluation and validation of proof of concept and mode of action for non-clinical research and early clinical development.
The patient-derived tumor xenograft (PDX) model is attracting worldwide attention for its high predictive ability for clinical efficacy as a tumor-bearing model similar to that of humans. The Japanese PDX (J-PDX) Library is being constructed to accelerate drug discovery and development research, eliminate drug lag, and revolutionize cancer treatment in Japan.
As described above, we are engaged in translational research in drug discovery and development through the development of basic pharmacokinetic, pharmacodynamic, and pharmacogenetic analysis by introducing innovative technologies and non-clinical studies using the J-PDX library.
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 analyses, novel Molecular Drug Imaging systems, and the J-PDX library.
Research Activities
1) PK/PD 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 has 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 system, molecular drug imaging system, and the originally developed NGS PGx panel. Moreover, by collaborating with 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 living body. Our laboratory has focused on the molecular process of anticancer drugs and various corresponding 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. We are also attempting drug concentration analysis at the cell level. We employed newly developed fluorescent nano-particle (PID). Using the PID method and multicolor fluorescent imaging, we expect to clarify the precise mode of action in antibody drugs.
3) J-PDX Project
Registration of the J-PDX library began in 2018. By March 2023, over 1880 registrations and more than 592 PDXs were established, making it the largest PDX library in Japan. The J-PDX library is being utilized for drug discovery and development research in collaboration with many academic institutions and pharmaceutical companies.
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 analyses, molecular drug imaging techniques, and establishment of the 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 2022
Journal
1. Higashiyama M, Motoi N, Yotsukura M, Yoshida Y, Nakagawa K, Yagishita S, Shirasawa M, Yoshida T, Shiraishi K, Kohno T, Ohe Y, Watanabe SI. Clinicopathological characteristics and molecular analysis of lung cancer associated with ciliated muconodular papillary tumor/bronchiolar adenoma. Pathology international, 73:188-197, 2023
2. Higashiyama RI, Yoshida T, Yagishita S, Hamada A. In Response: Letter Received From Dr. Charles Ricordel Titled "Safety of Extended-Interval Dosing Strategy of Immune Checkpoint Inhibitors for Advanced NSCLC". Journal of thoracic oncology, 18:e16-e17, 2023
3. Fukuda A, Yoshida T, Yagishita S, Shiotsuka M, Kobayashi O, Iwata S, Umeguchi H, Yanagida M, Irino Y, Masuda K, Shinno Y, Okuma Y, Goto Y, Horinouchi H, Hamada A, Yamamoto N, Ohe Y. Real-world Data on the Incidence of Coronavirus Disease (COVID-19) in Patients With Advanced Thoracic Cancer During the Early Phase of the Pandemic in Japan. Anticancer research, 43:919-926, 2023
4. Akagi K, Yagishita S, Ohuchi M, Hayashi Y, Takeyasu Y, Masuda K, Shinno Y, Okuma Y, Yoshida T, Goto Y, Horinouchi H, Yamamoto N, Mukae H, Ohe Y, Hamada A. Impact of ramucirumab pharmacokinetics in combination with docetaxel on the efficacy and survival in patients with advanced non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands), 178:247-253, 2023
5. Yagishita S, Nishikawa T, Yoshida H, Shintani D, Sato S, Miwa M, Suzuki M, Yasuda M, Ogitani Y, Jikoh T, Yonemori K, Hasegawa K, Hamada A. Co-clinical study of [fam-] trastuzumab deruxtecan (DS8201a) in patient-derived xenograft models of uterine carcinosarcoma and its association with clinical efficacy. Clinical cancer research, 29:2239-2249, 2023
6. Nishikawa T, Hasegawa K, Matsumoto K, Mori M, Hirashima Y, Takehara K, Ariyoshi K, Kato T, Yagishita S, Hamada A, Kawasaki M, Kawashima S, Tomatsuri S, Nagasaka Y, Yoshida H, Machida R, Hirakawa A, Nakamura K, Yonemori K. Trastuzumab Deruxtecan for Human Epidermal Growth Factor Receptor 2-Expressing Advanced or Recurrent Uterine Carcinosarcoma (NCCH1615): The STATICE Trial. Journal of clinical oncology, 41:2789-2799, 2023
7. Tanaka S, Umezawa J, Yamaji T, Abe SK, Hamada A, Kobayashi O, Ushijima T, Inoue M. SARS-CoV-2 Antibody Response to Symptoms Indicative of COVID-19 in a Non-Infected Population in Japan: a Cross-Sectional Study. Japanese journal of infectious diseases, 76:46-54, 2023
8. Torasawa M, Yoshida T, Yagishita S, Shimoda Y, Shirasawa M, Matsumoto Y, Masuda K, Shinno Y, Okuma Y, Goto Y, Horinouchi H, Yamamoto N, Takahashi K, Ohe Y. Nivolumab versus pembrolizumab in previously-treated advanced non-small cell lung cancer patients: A propensity-matched real-world analysis. Lung cancer (Amsterdam, Netherlands), 167:49-57, 2022
9. Ohuchi M, Yagishita S, Jo H, Akagi K, Inaba Higashiyama R, Masuda K, Shinno Y, Okuma Y, Yoshida T, Goto Y, Horinouchi H, Makino Y, Yamamoto N, Ohe Y, Hamada A. Early change in the clearance of pembrolizumab reflects the survival and therapeutic response: A population pharmacokinetic analysis in real-world non-small cell lung cancer patients. Lung cancer (Amsterdam, Netherlands), 173:35-42, 2022
10. Zhang Y, Goto Y, Yagishita S, Shinno Y, Mizuno K, Watanabe N, Yamamoto Y, Ota N, Ochiya T, Fujita Y. Machine learning-based exceptional response prediction of nivolumab monotherapy with circulating microRNAs in non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands), 173:107-115, 2022
11. Katsuya Y, Kitano S, Yamashita M, Ouchi M, Yagishita S, Hamada A, Nakamura H, Hosoda F, Shibata T, Motoi N, Nakayama T, Seto T, Umemura S, Hosomi Y, Satouchi M, Nishio M, Kozuki T, Hida T, Ohe Y, Horinouchi H. Comprehensive biomarker analysis from phase II study of nivolumab in patients with thymic carcinoma. Frontiers in oncology, 12:966527, 2022
12. Higashiyama RI, Yoshida T, Yagishita S, Ohuchi M, Sakiyama N, Torasawa M, Shirasawa M, Masuda K, Shinno Y, Matsumoto Y, Okuma Y, Goto Y, Horinouchi H, Yamamoto N, Hamada A, Ohe Y. Safety Implications of Switching Pembrolizumab Dosage From 200 mg Every 3 Weeks to 400 mg Every 6 Weeks in Patients With Advanced NSCLC. Journal of thoracic oncology, 17:1227-1232, 2022
13. Ryu S, Hayashi Y, Yagishita S, Takahashi A, Yokoi A, Ohuchi M, Hamada A. Development of an analytical method to determine E7130 concentration in mouse plasma by micro-sampling using ultra-performance liquid chromatography-high resolution mass spectrometry. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences, 1207:123366, 2022
14. Iwamoto N, Koguchi Y, Yokoyama K, Hamada A, Yonezawa A, Piening BD, Tran E, Fox BA, Redmond WL, Shimada T. A rapid and universal liquid chromatograph-mass spectrometry-based platform, refmAb-Q nSMOL, for monitoring monoclonal antibody therapeutics. The Analyst, 147:4275-4284, 2022