Annual Report 2019
Division of Cancer Pathophysiology
Yasuhito Uezono, Kanako Miyano, Sadamoto Zenda, Sei Manabe, Yusuke Mizobuchi, Miki Nonaka, Junko Ezuka, Kiyoshi Terawaki, Katsuya Ohbuchi, Chika Miyagi, Tohru Yokoyama, Satoshi Murakami, Hideya Kokubun, Shigeto Hirayama, Seiji Shiraishi, Yuriko Fujii, Yui Kuroda, Akane Komatsu, Eiko Uezono, Katsuyuki Oki, Yuji Shimogawa, Yasuhiro Nose, Seiichi Yoshihara, Kurumi Kishimoto
Introduction
Since its establishment in January 2009, the Division of Cancer Pathophysiology has focused on two major research issues: 1) the improvement of the quality of life (QOL) of patients with cancer suffering from severe or intolerable pain, and 2) the prevention and development of novel treatments for cancer cachexia symptoms. On the basis of the Second Basic Plan to Promote Cancer Control Programs since 2016, basic to clinical, and clinical to basic translational research with the clinical laboratory groups comprises our main research protocols and has been ongoing. Since 2015, the chief of this division holds posts both in the Division of Supportive Care Research in the Exploratory Oncology Research and Clinical Trial Center (EPOC) (for phase I clinical studies) and the Innovation Center for Supportive, Palliative and Psychosocial Care at the NCCH (for phase II and III clinical studies), to accelerate the development of innovative medicines for cancer patients.
The Team and What We Do
A weekly conference/research seminar is held with all members including laboratory staff and graduate and undergraduate students at the Division of Cancer Pathophysiology.
Research activities
1. Translational research to innovate new strategies to improve pain analgesia in cancer patients
The aim of our studies is to develop new therapies for chemotherapy-induced peripheral neuropathy and refractory cancer pain, both of which make the QOL of cancer patients even worse. One of the targets is oral stomatitis induced by chemotherapy and/or radiotherapy.
Cancer patients who undergo chemotherapy, radiotherapy and terminal palliative care often have a wide range of stomatitis, which induces severe pain and limits the fundamental basics of life such as eating, drinking, and talking. Since 2015, we have been developing a new painkiller drug for stomatitis, namely “compound X”. Based on our research results, the new painkiller compound X was found to remove oral pain without changing the texture and taste of food. The project was supported intellectually and financially by the Project Promoting Support for Drug Discovery from the Japan Agency for Medical Research and Development (AMED). Compound X has been successfully licensed out to a pharmaceutical company, Maruho Co., Ltd. and collaborative research with Maruho Co., Ltd. is now underway.
The second target is chronic and intolerable pain. In collaboration with the Department of Lipid Signaling and the National Center for Global Health and Medicine (NCGM), we discovered that knocking out of inducible platelet-activating factor (PAF) synthase type 2 suppressed neuropathic pain. We are working together to find novel PAF receptor and PAF synthase antagonists with support from the Project for Cancer Research and Therapeutic Evolution (P-CREATE) from AMED. Accordingly, we found several specific antagonists for both PAF receptors and PAF synthase type 2 in collaboration with pharmaceutical companies.
2. Prevention and decrease of the cachexic symptoms by orexigenic hormone acyl ghrelin and des-acyl ghrelin
We established novel cancer cachexia animal models, and then undertook molecular and cellular analyses to identify the mechanisms of action of expected compounds to improve the QOL of patients suffering from cancer cachexia. We found that both acyl ghrelin and des-acyl ghrelin, which is ghrelin with the acyl residue removed, improved cachexia-induced cardiac dysfunction in a mouse cachexic model. Also, we identified a novel receptor specific for des-acyl ghrelin, expected to be a novel target for drug innovation, and got a patent for it with Kagoshima University.
3. Development of biomarkers predicting the onset of severe postoperative delirium following surgical cancer resection
Delirium is a common, serious, and potentially fatal disorder that affects as many as 50% of elderly people in hospitals. It represents an acute response to events such as surgery, and is itself a risk factor for cognitive decline, institutionalization and increased mortality. Comorbid delirium interferes with the surgical outcome and palliative care in cancer patients. However, the biological causality of delirium remains unknown and we have not yet acquired standardised prevention. Accordingly, we suggest developing biomarkers to predict postoperative delirium by metabolomics, immunological, gene regulation, and gene expression analyses targeting an excessive immune reaction following surgical cancer resection. Innovation of predictive biomarkers for postoperative delirium will highly contribute to supportive care of cancer patients undergoing surgery with the development of early and appropriate intervention. At present, we have found several possible biomarkers with both metabolome assay and comprehensive cytokine screening assay using blood from cancer patients.
Education
Two postdoctoral fellows, four graduates and three master's degree and 10 undergraduate students have been trained in the field of cancer, supportive and palliative care at the Division of Cancer Pathophysiology.
Future prospects
The goal of the Division of Cancer Pathophysiology is to improve the QOL of cancer patients, hopefully by overcoming unmet medical needs.
List of papers published in 2019
Journal
1. Miyano K, Eto M, Hitomi S, Matsumoto T, Hasegawa S, Hirano A, Nagabuchi K, Asai N, Uzu M, Nonaka M, Omiya Y, Kaneko A, Ono K, Fujii H, Higami Y, Kono T, Uezono Y. The Japanese herbal medicine Hangeshashinto enhances oral keratinocyte migration to facilitate healing of chemotherapy-induced oral ulcerative mucositis. Sci Rep, 10:625, 2020
2. Miyano K, Ohshima K, Suzuki N, Furuya S, Yoshida Y, Nonaka M, Higami Y, Yoshizawa K, Fujii H, Uezono Y. Japanese Herbal Medicine Ninjinyoeito Mediates Its Orexigenic Properties Partially by Activating Orexin 1 Receptors. Front Nutr, 7:5, 2020
3. Miyano K, Ohbuchi K, Sudo Y, Minami K, Yokoyama T, Yamamoto M, Uzu M, Nonaka M, Shiraishi S, Murata H, Higami Y, Uezono Y. A novel method for evaluating activity of transient receptor potential channels using a cellular dielectric spectroscopy. J Pharmacol Sci, 143:320-324, 2020
4. Masamune A, Kotani H, Sörgel FL, Chen JM, Hamada S, Sakaguchi R, Masson E, Nakano E, Kakuta Y, Niihori T, Funayama R, Shirota M, Hirano T, Kawamoto T, Hosokoshi A, Kume K, Unger L, Ewers M, Laumen H, Bugert P, Mori MX, Tsvilovskyy V, Weißgerber P, Kriebs U, Fecher-Trost C, Freichel M, Diakopoulos KN, Berninger A, Lesina M, Ishii K, Itoi T, Ikeura T, Okazaki K, Kaune T, Rosendahl J, Nagasaki M, Uezono Y, Algül H, Nakayama K, Matsubara Y, Aoki Y, Férec C, Mori Y, Witt H, Shimosegawa T. Variants That Affect Function of Calcium Channel TRPV6 Are Associated With Early-Onset Chronic Pancreatitis. Gastroenterology, 158:1626-1641.e8, 2020
5. Okubo R, Kinoshita T, Katsumata N, Uezono Y, Xiao J, Matsuoka YJ. Impact of chemotherapy on the association between fear of cancer recurrence and the gut microbiota in breast cancer survivors. Brain Behav Immun, 85:186-191, 2020
6. Horishita T, Ogata Y, Horishita R, Fukui R, Moriwaki K, Ueno S, Yanagihara N, Uezono Y, Sudo Y, Minami K. Carvacrol inhibits the neuronal voltage-gated sodium channels Na(v)1.2, Na(v)1.6, Na(v)1.3, Na(v)1.7, and Na(v)1.8 expressed in Xenopus oocytes with different potencies. J Pharmacol Sci, 142:140-147, 2020
7. Matsubara T, Satoh K, Homma T, Nakagaki T, Yamaguchi N, Atarashi R, Sudo Y, Uezono Y, Ishibashi D, Nishida N. Prion protein interacts with the metabotropic glutamate receptor 1 and regulates the organization of Ca2+ signaling. Biochem Biophys Res Commun, 525:447-454, 2020
8. Yatsuoka W, Ueno T, Miyano K, Uezono Y, Enomoto A, Kaneko M, Ota S, Soga T, Sugimoto M, Ushijima T. Metabolomic profiling reveals salivary hypotaurine as a potential early detection marker for medication-related osteonecrosis of the jaw. PLoS One, 14:e0220712, 2019
9. Uzu M, Nonaka M, Miyano K, Sato H, Kurebayashi N, Yanagihara K, Sakurai T, Hisaka A, Uezono Y. A novel strategy for treatment of cancer cachexia targeting xanthine oxidase in the brain. J Pharmacol Sci, 140:109-112, 2019
10. Manabe S, Miyano K, Fujii Y, Ohshima K, Yoshida Y, Nonaka M, Uzu M, Matsuoka Y, Sato T, Uezono Y, Morimatsu H. Possible biased analgesic of hydromorphone through the G protein-over beta-arrestin-mediated pathway: cAMP, CellKey, and receptor internalization analyses. J Pharmacol Sci, 140:171-177, 2019
11. Miyano K, Shiraishi S, Minami K, Sudo Y, Suzuki M, Yokoyama T, Terawaki K, Nonaka M, Murata H, Higami Y. Carboplatin Enhances the Activity of Human Transient Receptor Potential Ankyrin 1 through the Cyclic AMP-Protein Kinase A-A-Kinase Anchoring Protein (AKAP) Pathways. Int J Mol Sci, 20:E3271, 2019
12. Horigome A, Okubo R, Hamazaki K, Kinoshita T, Katsumata N, Uezono Y, Xiao JZ, Matsuoka YJ. Association between blood omega-3 polyunsaturated fatty acids and the gut microbiota among breast cancer survivors. Benef Microbes, 10:751-758, 2019
13. Uzu M, Nonaka M, Miyano K, Sato H, Kurebayashi N, Yanagihara K, Sakurai T, Hisaka A, Uezono Y. A novel strategy for treatment of cancer cachexia targeting xanthine oxidase in the brain. J Pharmacol Sci, 140:109-112, 2019
14. Manabe S, Miyano K, Fujii Y, Ohshima K, Yoshida Y, Nonaka M, Uzu M, Matsuoka Y, Sato T, Uezono Y, Morimatsu H. Possible biased analgesic of hydromorphone through the G protein-over β-arrestin-mediated pathway: cAMP, CellKey, and receptor internalization analyses. J Pharmacol Sci, 140:171-177, 2019
15. Miyano K, Shiraishi S, Minami K, Sudo Y, Suzuki M, Yokoyama T, Terawaki K, Nonaka M, Murata H, Higami Y, Uezono Y. Carboplatin Enhances the Activity of Human Transient Receptor Potential Ankyrin 1 through the Cyclic AMP-Protein Kinase A-A-Kinase Anchoring Protein (AKAP) Pathways. Int J Mol Sci, 20:3271, 2019
16. Yatsuoka W, Ueno T, Miyano K, Uezono Y, Enomoto A, Kaneko M, Ota S, Soga T, Sugimoto M, Ushijima T. Metabolomic profiling reveals salivary hypotaurine as a potential early detection marker for medication-related osteonecrosis of the jaw. PLoS One, 14:e0220712, 2019
17. Karaki F, Umemoto S, Ashizawa K, Oki T, Sato N, Ogino T, Ishibashi N, Someya R, Miyano K, Hirayama S, Uezono Y, Fujii H. A New Lead Identification Strategy: Screening an sp(3) -rich and Lead-like Compound Library Composed of 7-Azanorbornane Derivatives. ChemMedChem, 14:1840-1848, 2019