Annual Report 2017

Yasuhito Uezono, Kanako Miyano, Sadamoto Zenda, Sei Manabe, Miki Nonaka, Junko Ezuka, Miaki Uzu, Kiyoshi Terawaki, Katsuya Ohbuchi, Chika Miyagi, Koichiro Minami, Tohru Yokoyama, Satoshi Murakami, Hideya Kokubun, Shigeto Hirayama, Yoshiyuki Nagumo, Seiji Shiraishi, Yuriko Fujii, Daisuke Nakayama, Yoshiyuki Meguro, Moeko Eto, Bunsei Yamamoto

Introduction

  Since its establishment in January 2009, the Division of Cancer Pathophysiology has focused on two major research issues regarding 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 in 2016, basic to clinical, and clinical to basic translational collaborative research with the clinical laboratory groups comprises our main research protocols and has been ongoing. Since 2015, the chief of this division holds both the posts in the Division of Supportive Care Research - the Exploratory Oncology Research and Clinical Trial Center (EPOC) (for phase I clinical study) and the Innovation Center for Supportive, Palliative and Psychosocial Care - the National Cancer Center Hospital (NCCH) (for phase II and III clinical studies), to accelerate the development of innovative medicines for cancer patients.

Our team and what we do

 A weekly conference/research seminar is held with all members including laboratory staff and 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. On the clinical side, the local anesthetic lidocaine is normally used for the relief of pain in cancer patients with stomatitis. However, lidocaine removes

not only pain but also the ability to discriminate taste and texture, since it non-selectively suppresses the activation of all neurons by blocking the voltage-gated Na+ channels. Therefore, a novel analgesic drug, which selectively blocks the pain-related neuron alone, is required to allow

patients to eat without losing or changing the taste and texture of food. Since 2015, we have been developing a new pain-killer drug for stomatitis, namely "compound X", and evaluated the intensity of oral pain using newly established stomatitis model animals by our research groups. With the model, lidocaine not only inhibited pain but also caused numbness in normal oral mucosa, however, the compound X only suppressed the pain in the ulcer without effects on normal tissues. On the basis of our basic research results, we have been developing "the new pain-killer compound X, which can remove the oral pain without changing the texture and taste of food" for cancer patients with severe painful stomatitis, with intellectual and financial support of the Project Promoting Support for Drug Discovery from the Japan Agency for Medical Research and Development (AMED).

 The second target is chronic and intolerable pain. We discovered that knocking out of inducible platelet-activating factor (PAF) synthase type 2 inhibited neuropathic pain, collaborated with the members of the Department of Lipid Signaling, the National Center for Global Health and Medicine (NCGM). We are working each other to find novel PAF receptor and PAF synthase antagonists with the support of the Project for Cancer Research and Therapeutic Evolution (P-CREATE) from AMED. We just found several specific antagonists for PAF synthase type 2 with members of NCGM.

2. Prevention and decrease of the cachexic symptoms by Japanese traditional KAMPO medicines or 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 the expected compounds to improve the QOL of patients suffering from cancer cachexia. We found that a Japanese Kampo (traditional Oriental) medicine "rikkunshito" usually administered for the prevention of gastritis, nausea, and vomiting, improved the symptoms of cancer cachexia by increasing orexigenic hormone, ghrelin-

mediated signaling. In addition to rikkunshito, we found both ghrelin and des-acyl ghrelin which is removed acyl residue from ghrelin, improved the cachexia-induced cardiac dysfunction.

 We also demonstrated that rikkunshito prolonged survival in mouse models by activation of ghrelin signal and subsequent sirtuin 1 signal, the important protein for longevity, suggesting that drugs that enhance ghrelin-mediated signaling may be helpful to extend health and lifespan as well as to improve cancer cachexia symptoms.

Education

 One postdoctoral fellow, two graduate and 20 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 January 2017 - March 2018

Journal

 1. Mori T, Kuzumaki N, Arima T, Narita M, Tateishi R, Kondo T, Hamada Y, Kuwata H, Kawata M, Yamazaki M, Sugita K, Matsuzawa A, Baba K, Yamauchi T, Higashiyama K, Nonaka M, Miyano K, Uezono Y. Usefulness for the combination of G-protein- and beta-arrestin-biased ligands of mu-opioid receptors: Prevention of antinociceptive tolerance. Mol Pain, 13:1.74481E+15, 2017

 2. Terawaki K, Kashiwase Y, Sawada Y, Hashimoto H, Yoshimura M, Ohbuchi K, Sudo Y, Suzuki M, Miyano K, Shiraishi S, Higami Y, Yanagihara K, Hattori T, Kase Y, Ueta Y, Uezono Y. Development of ghrelin resistance in a cancer cachexia rat model using human gastric cancer-derived 85As2 cells and the palliative effects of the Kampo medicine rikkunshito on the model. PLoS One, 12:e0173113, 2017

 3. Akiyama Y, Yoshimura M, Nishimura K, Nishimura H, Sonoda S, Ueno H, Mitojima Y, Saito R, Maruyama T, Nonaka Y, Hashimoto H, Uezono Y, Hirata K, Ueta Y. Activation of central nesfatin-1/NucB2 after intraperitoneally administered cisplatin in rats. Biochem Biophys Res Commun, 490:794-799, 2017

 4. Nonaka M, Kurebayashi N, Murayama T, Sugihara M, Terawaki K, Shiraishi S, Miyano K, Hosoda H, Kishida S, Kangawa K, Sakurai T, Uezono Y. Therapeutic potential of ghrelin and des-acyl ghrelin against chemotherapy-induced cardiotoxicity. Endocr J, 64:S35-S39, 2017

 5. Ohnishi S, Watari H, Kanno M, Ohba Y, Takeuchi S, Miyaji T, Oyamada S, Nomura E, Kato H, Sugiyama T, Asaka M, Sakuragi N, Yamaguchi T, Uezono Y, Iwase S. Additive effect of rikkunshito, an herbal medicine, on chemotherapy-induced nausea, vomiting, and anorexia in uterine cervical or corpus cancer patients treated with cisplatin and paclitaxel: results of a randomized phase II study (JORTC KMP-02). J Gynecol Oncol, 28:e44, 2017

 6. Shindou H, Shiraishi S, Tokuoka SM, Takahashi Y, Harayama T, Abe T, Bando K, Miyano K, Kita Y, Uezono Y, Shimizu T. Relief from neuropathic pain by blocking of the platelet-activating factor-pain loop. FASEB J, 31:2973-2980, 2017

 7. Sakai H, Tabata S, Kimura M, Yabe S, Isa Y, Kai Y, Sato F, Yumoto T, Miyano K, Narita M, Uezono Y. Active Ingredients of Hange-shashin-to, Baicalelin and 6-Gingerol, Inhibit 5-Fluorouracil-Induced Upregulation of CXCL1 in the Colon to Attenuate Diarrhea Development. Biol Pharm Bull, 40:2134-2139, 2017

 8. Horishita T, Yanagihara N, Ueno S, Okura D, Horishita R, Minami T, Ogata Y, Sudo Y, Uezono Y, Sata T, Kawasaki T. Antidepressants inhibit Nav1.3, Nav1.7, and Nav1.8 neuronal voltage-gated sodium channels more potently than Nav1.2 and Nav1.6 channels expressed in Xenopus oocytes. Naunyn Schmiedebergs Arch Pharmacol, 390:1255-1270, 2017