Division of Cancer Pathophysiology

Yasuhito Uezono, Kanako Miyano, Seiji Shiraishi, Sadamoto Zenda, Miki Nonaka, Yoshiyuki Meguro, Junko Ezuka, Kiyoshi Terawaki, Katsuya Ohbuchi, Chika Shimobori, Koichiro Minami, Tohru Yokoyama, Satoshi Murakami, Hideya Kokubun, Shigeto Hirayama, Yoshiyuki Nagumo, Moeko Eto, Hoko Ohguri, Tomoko Matsude, Takamichi Arima, Mio Sekiguchi, Airi Mizukami, Naoto Ishibashi, Yuka Ishibashi, Kota Imai, Yoko Omichi, Takumi Ogino, Rika Hachiya, Ayane Hirano, 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. Based on the 2nd Basic Plan to Promote Cancer Control Programs in 2012, and the prospective 3rd plan in 2017, basic to clinical, and also 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 Exploratory Oncology Research and Clinical Trial Center (for phase I clinical study) and Innovation Center for Supportive, Palliative and Psychosocial Care (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 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. 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. Based on 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 from Japan Agency for medical Research and Development (AMED).

The second target is severe pain such as one with bone-metastasized patients. We showed that a platelet-activating factor (PAF) receptor antagonists produced profound and long lasting anti-allodynia effects in several different neuropathic pain models in mice. We have demonstrated that the PAF antagonist showed extremely excellent analgesic effects on both the bone-metastasized cancer pain model and also the chemotherapy-induced peripheral neuropathy model. Further, we discovered that knocking out of inducible PAF synthase type 2 inhibited neuropathic pain with the members of the Department of Lipid Signaling, the National Center for Global Health and Medicine. We are collaborating with 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.

2.Prevention and decrease of the cachexic symptoms or chemotherapy-induced side effects by Japanese traditional KAMPO medicines

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. In addition to rikkunshito, we analyzed and summarized the action mechanisms of other traditional Japanese Kampo medicines to improve chemotherapy-induced side effects such as pain and allodynia.

We recently 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 potentiation of this signal with rikkunshito may be helpful to extend health and lifespan.

Education

One postdoctoral fellow, two graduate students and 12 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 2016

Journal

1.Miyano K, Ueno T, Yatsuoka W, Uezono Y. Treatment for Cancer Patients with Oral Mucositis: Assessment Based on the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer in International Society of Oral Oncology (MASCC/ISOO) in 2013 and Proposal of Possible Novel Treatment with a Japanese Herbal Medicine. Curr Pharm Des, 22:2270-2278, 2016

2.Yamaguchi K, Ono K, Hitomi S, Ito M, Nodai T, Goto T, Harano N, Watanabe S, Inoue H, Miyano K, Uezono Y, Matoba M, Inenaga K. Distinct TRPV1- and TRPA1-based mechanisms underlying enhancement of oral ulcerative mucositis-induced pain by 5-fluorouracil. Pain, 157:1004-1020, 2016

3.Doi S, Mori T, Uzawa N, Arima T, Takahashi T, Uchida M, Yawata A, Narita M, Uezono Y, Suzuki T, Narita M. Characterization of methadone as a beta-arrestin-biased mu-opioid receptor agonist. Mol Pain, 12:2016

4.Ohbuchi K, Miyagi C, Suzuki Y, Mizuhara Y, Mizuno K, Omiya Y, Yamamoto M, Warabi E, Sudo Y, Yokoyama A, Miyano K, Hirokawa T, Uezono Y. Ignavine: a novel allosteric modulator of the mu opioid receptor. Sci Rep, 6:31748, 2016

5.Fujitsuka N, Asakawa A, Morinaga A, Amitani MS, Amitani H, Katsuura G, Sawada Y, Sudo Y, Uezono Y, Mochiki E, Sakata I, Sakai T, Hanazaki K, Yada T, Yakabi K, Sakuma E, Ueki T, Niijima A, Nakagawa K, Okubo N, Takeda H, Asaka M, Inui A. Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1. Mol Psychiatry, 21:1613-1623, 2016

6.Tsuchiya K, Kubota K, Ohbuchi K, Kaneko A, Ohno N, Mase A, Matsushima H, Yamamoto M, Miyano K, Uezono Y, Kono T. Transient receptor potential ankyrin 1 agonists improve intestinal transit in a murine model of postoperative ileus. Neurogastroenterol Motil, 28:1792-1805, 2016

7.Kajitani N, Miyano K, Okada-Tsuchioka M, Abe H, Itagaki K, Hisaoka-Nakashima K, Morioka N, Uezono Y, Takebayashi M. Identification of Lysophosphatidic Acid Receptor 1 in Astroglial Cells as a Target for Glial Cell Line-derived Neurotrophic Factor Expression Induced by Antidepressants. J Biol Chem, 291:27364-27370, 2016

8.Murakami S, Herai M, Suzuki S, Fujii T, Tanaka H, Shinozaki M, Kokubun H, Akagi T, Uezono Y, Murakaimi-Ando Y, Shiraishi S, Matoba M. Plasma concentration of oxycodone and pain during hemodialysis in a patient with cancer. J Palliat Care Med, 6:1000252, 2016

9.Muramatsu S, Shiraishi S, Miyano K, Sudo Y, Toda A, Mogi M, Hara M, Yokoyama A, Kawasaki Y, Taniguchi M, Uezono Y. Metabolism of AM404 From Acetaminophen at Human Therapeutic Dosages in the Rat Brain. Anesth Pain Med, 6:e32873, 2016

10.Murakami S, Sudo Y, Miyano K, Nishimura H, Matoba M, Shiraishi S, Konno H, Uezono Y. Tris-hydroxymethyl-aminomethane enhances capsaicin-induced intracellular Ca2+ influx through transient receptor potential V1 (TRPV1) channels. J Pharmacol Sci, 130:72-77, 2016

11.Tagami K, Kashiwase Y, Yokoyama A, Nishimura H, Miyano K, Suzuki M, Shiraishi S, Matoba M, Ohe Y, Uezono Y. The atypical antipsychotic, olanzapine, potentiates ghrelin-induced receptor signaling: An in vitro study with cells expressing cloned human growth hormone secretagogue receptor. Neuropeptides, 58:93-101, 2016

Book

1.Uezono Y, Miyano K. Pain and Herbal Medicine: Effectiveness of Japanese Kampo Medicines on Pains Associated with Cancer Patients. In: Inui A (ed), Herbal Medicines, Methods in Pharmacology and Toxicology, USA, Springer Science, pp 19-36, 2016