Annual Report 2021
Division of Molecular Pharmacology
Akinobu Hamada, Shigehiro Yagishita, Tomomi Yoshino, Mikiko Suzuki, Shoraku Ryu, Mayu Ohuchi, Chisato Oto, Ako Takahashi, Kazumasa Akagi, Chiaki Ushie, Ai Umeda, Yu Nagai
Introduction
Clinical pharmacology research is an important step in drug discovery and development research, bridging the gap (the so-called “Death Valley”) from non-clinical research to 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 Department of Pharmacology and Therapeutics, are promoting the evaluation of drug distribution in target tissues (tumor local PK), which cannot be evaluated 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 information 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 in 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. A 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/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 of 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 (PIDs). Using the PID method and multicolor fluorescent imaging, we expect to clarify the precise modes of action in antibody drugs.
3) J-PDX Project
Registration for the J-PDX library began in 2018, and by December 2021, over 1,400 registrations and more than 400 PDXs had been 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 from the 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 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 2021
Journal
1. Jo H, Yagishita S, Hayashi Y, Ryu S, Suzuki M, Kohsaka S, Ueno T, Matsumoto Y, Horinouchi H, Ohe Y, Watanabe SI, Motoi N, Yatabe Y, Mano H, Takahashi K, Hamada A. Comparative Study on the Efficacy and Exposure of Molecular Target Agents in Non-small Cell Lung Cancer PDX Models with Driver Genetic Alterations. Molecular cancer therapeutics, 21:359-370, 2022
2. Jo H, Yoshida T, Horinouchi H, Yagishita S, Matsumoto Y, Shinno Y, Okuma Y, Goto Y, Yamamoto N, Takahashi K, Motoi N, Ohe Y. Prognostic significance of cachexia in advanced non-small cell lung cancer patients treated with pembrolizumab. Cancer immunology, immunotherapy: CII, 71:387-398, 2022
3. Mizugaki H, Oizumi S, Fujita Y, Harada T, Nakahara Y, Takashina T, Ko R, Watanabe K, Hotta T, Minemura H, Saeki S, Asahina H, Nakamura K, Nakamura H, Hosoda F, Yagishita S, Hamada A. Pharmacokinetic and pharmacogenomic analysis of low-dose afatinib treatment in elderly patients with EGFR mutation-positive non-small cell lung cancer. European journal of cancer (Oxford, England: 1990), 160:227-234, 2022
4. Nitani C, Hara J, Kawamoto H, Taguchi T, Kimura T, Yoshimura K, Hamada A, Kitano S, Hattori N, Ushijima T, Ono H, Nakamoto M, Higuchi T, Sato A. Phase I study of tamibarotene monotherapy in pediatric and young adult patients with recurrent/refractory solid tumors. Cancer Chemother Pharmacol, 88:99-107, 2021
5. Ohno M, Hayashi Y, Aikawa H, Hayashi M, Miyakita Y, Takahashi M, Matsushita Y, Yoshida A, Satomi K, Ichimura K, Hamada A, Narita Y. Tissue 2-Hydroxyglutarate and Preoperative Seizures in Patients With Diffuse Gliomas. Neurology, 97:e2114-e2123, 2021
6. Yazaki S, Yoshida T, Kojima Y, Yagishita S, Nakahama H, Okinaka K, Matsushita H, Shiotsuka M, Kobayashi O, Iwata S, Narita Y, Ohba A, Takahashi M, Iwasa S, Kobayashi K, Ohe Y, Yoshida T, Hamada A, Doi T, Yamamoto N. Difference in SARS-CoV-2 Antibody Status Between Patients With Cancer and Health Care Workers During the COVID-19 Pandemic in Japan. JAMA oncology, 7:1141-1148, 2021
7. Morita C, Yoshida T, Shirasawa M, Masuda K, Matsumoto Y, Shinno Y, Yagishita S, Okuma Y, Goto Y, Horinouchi H, Yamamoto N, Motoi N, Yatabe Y, Ohe Y. Clinical characteristics of advanced non-small cell lung cancer patients with EGFR exon 20 insertions. Scientific reports, 11:18762, 2021
8. Suzuki M, Yagishita S, Sugihara K, Ogitani Y, Nishikawa T, Ohuchi M, Teishikata T, Jikoh T, Yatabe Y, Yonemori K, Tamura K, Hasegawa K, Hamada A. Visualization of Intratumor Pharmacokinetics of [fam-] Trastuzumab Deruxtecan (DS-8201a) in HER2 Heterogeneous Model Using Phosphor-integrated Dots Imaging Analysis. Clinical cancer research: an official journal of the American Association for Cancer Research, 27:3970-3979, 2021
9. Taguchi K, Hayashi Y, Ohuchi M, Yamada H, Yagishita S, Enoki Y, Matsumoto K, Hamada A. Augmented clearance of nivolumab is associated with renal functions in chronic renal disease model rats. Drug metabolism and disposition: the biological fate of chemicals, 2021
10. Hayashi Y, Ohuchi M, Ryu S, Yagishita S, Hamada A. A procedure for method development and protein binding ratio as the indicator of sensitivity with anticancer agents on MALDI mass spectrometry imaging. Drug metabolism and pharmacokinetics, 38:100385, 2021
11. 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. Clinical lung cancer, 22:282-291.e6, 2021
12. 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 science, 112:2006-2019, 2021
13. 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 science, 112:2454-2466, 2021