Annual Report 2024
Division of Molecular Pharmacology /
Department of Pharmacology and Therapeutic
Akinobu Hamada, Shigehiro Yagishita, Tomomi Yoshino, Shoraku Ryu, Mayu Ohuchi, Ako Takahashi, Misato Jinno, 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 2025, 2,206 registrations and 668 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 2024
Journal
1. Shirasawa M, Yoshida T, Matsutani T, Takeyasu Y, Goto N, Yagishita S, Kitano S, Kuroda H, Hida T, Kurata T, Ohe Y. Diversity of TCR repertoire predicts recurrence after CRT followed by durvalumab in patients with NSCLC. NPJ precision oncology, 9:17, 2025
2. Katsuya Y, Yoshida T, Takashima A, Yonemori K, Ohba A, Yazaki S, Yagishita S, Nakahama H, Kobayashi O, Yanagida M, Irino Y, Hamada A, Yamamoto N. Immunogenicity after vaccination of COVID-19 vaccines in patients with cancer: a prospective, single center, observational study. International journal of clinical oncology, 29:386-397, 2024
3. Sasaki A, Takeshima H, Yamashita S, Ichita C, Kawachi J, Naito W, Ohashi Y, Takeuchi C, Fukuda M, Furuichi Y, Yamamichi N, Ando T, Kobara H, Kotera T, Itoi T, Sumida C, Hamada A, Koizumi K, Ushijima T. Severe induction of aberrant DNA methylation by nodular gastritis in adults. Journal of gastroenterology, 59:442-456, 2024
4. Mori Y, Okimoto Y, Sakai H, Kanda Y, Ohata H, Shiokawa D, Suzuki M, Yoshida H, Ueda H, Sekizuka T, Tamura R, Yamawaki K, Ishiguro T, Mateos RN, Shiraishi Y, Yatabe Y, Hamada A, Yoshihara K, Enomoto T, Okamoto K. Targeting PDGF signaling of cancer-associated fibroblasts blocks feedback activation of HIF-1α and tumor progression of clear cell ovarian cancer. Cell reports. Medicine, 5:101532, 2024
5. Torasawa M, Yoshida T, Shiraishi K, Goto N, Ueno T, Ichikawa H, Yagishita S, Kohsaka S, Goto Y, Yatabe Y, Hamada A, Mano H, Ohe Y. Rapid Response to Lenvatinib and Disease Flare After Discontinuation in a Patient With Thymic Carcinoma Harboring KIT Exon 11 Mutation: A Case Report. JTO clinical and research reports, 5:100657, 2024
6. Kohsaka S, Yagishita S, Shirai Y, Matsuno Y, Ueno T, Kojima S, Ikeuchi H, Ikegami M, Kitada R, Yoshioka KI, Toshimitsu K, Tabata K, Yokoi A, Doi T, Yamamoto N, Owa T, Hamada A, Mano H. A molecular glue RBM39-degrader induces synthetic lethality in cancer cells with homologous recombination repair deficiency. NPJ precision oncology, 8:117, 2024
7. Otomo K, Omura T, Nozawa Y, Edwards SJ, Sato Y, Saito Y, Yagishita S, Uchida H, Watakabe Y, Naitou K, Yanai R, Sahara N, Takagi S, Katayama R, Iwata Y, Shiokawa T, Hayakawa Y, Otsuka K, Watanabe-Takano H, Haneda Y, Fukuhara S, Fujiwara M, Nii T, Meno C, Takeshita N, Yashiro K, Rosales Rocabado JM, Kaku M, Yamada T, Oishi Y, Koike H, Cheng Y, Sekine K, Koga JI, Sugiyama K, Kimura K, Karube F, Kim H, Manabe I, Nemoto T, Tainaka K, Hamada A, Brismar H, Susaki EA. descSPIM: an affordable and easy-to-build light-sheet microscope optimized for tissue clearing techniques. Nature communications, 15:4941, 2024
8. Yagishita S, Yamanaka Y, Kurata T, Watanabe K, Hosomi Y, Horinouchi H, Ohe Y, Nakahara Y, Naoki K, Asao T, Takahashi K, Saeki S, Sakagami T, Nakashima K, Tsubata Y, Fujita Y, Wakui H, Furuta M, Konishi JS, Ohuchi M, Ando Y, Mizugaki H, Hamada A. Multicenter Pharmacokinetic and Pharmacodynamic Study of Pembrolizumab for Non-small-Cell Lung Cancer in Patients Aged 75 Years and Older. Clinical pharmacology and therapeutics, 116:1042-1051, 2024
9. Nishikawa T, Kakunaga S, Tamura K, Ando M, Ozaki T, Kawai A, Ueda T, Kawasaki M, Tomatsuri S, Okamura N, Kamikura M, Hamada A, Yoshida A, Hirakawa A, Shibata T, Nakamura K, Yonemori K. Efficacy and safety of nivolumab monotherapy in patients with unresectable clear cell sarcoma and alveolar soft part sarcoma (OSCAR Trial/NCCH1510). Cancer, 130:3836-3844, 2024
10. Yagishita S, Goto Y, Nishio M, Akamatsu H, Hayashi H, Miura S, Tamada K, Kagamu H, Hamada A, Ohuchi M, Gemma A, Yoshino I, Misumi T, Hata A, Hara S, Kijima T, Masaki F, Iwasawa S, Nakagawa S, Tatsuno M, Mitsudomi T. Real-World Pharmacokinetics, Effectiveness, and Safety of Atezolizumab in Patients With Unresectable Advanced or Recurrent NSCLC: An Exploratory Study of J-TAIL. JTO clinical and research reports, 5:100683, 2024
11. Matsui K, Yagishita S, Hamada A. Need for Ethical Governance on the Implementation and Use of Patient-derived Xenograft (PDX) Models for Anti-cancer Drug Discovery and Development: Ethical Considerations and Policy Proposal. JMA journal, 7:605-609, 2024
12. Yamamoto G, Tanaka K, Kamata R, Saito H, Yamamori-Morita T, Nakao T, Liu J, Mori S, Yagishita S, Hamada A, Shinno Y, Yoshida T, Horinouchi H, Ohe Y, Watanabe SI, Yatabe Y, Kitai H, Konno S, Kobayashi SS, Ohashi A. WEE1 confers resistance to KRAS(G12C) inhibitors in non-small cell lung cancer. Cancer letters, 611:217414, 2024