新たなDDSを用いた多発性骨髄腫への新規治療法の開発

2015 Fiscal Year Annual Research Report

• Project/Area Number: 26640101
• Research Institution: The University of Tokyo
• Principal Investigator: 今井 浩三 東京大学, 医科学研究所, 特任研究員 (60117603)
• Co-Investigator(Kenkyū-buntansha): 安井 寛 東京大学, 医科学研究所, 特任准教授 (40448593)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Keywords: 多発性骨髄腫 / ＤＤＳ / 橋渡し研究 / 骨髄微小環境 / 免疫細胞 / 抗体医薬

Outline of Annual Research Achievements

当該研究では、多発性骨髄腫に有用なDrug delivery system (DDS)を考案するために、同疾患におけるDDS創薬の開発の課題を抽出し、それを克服するための基盤的研究を行った。研究者らは、これまでに同疾患で関わってきた多数のシーズ開発の経験から、多発性骨髄腫は骨髄を増殖の首座とする腫瘍であり、その微小環境の影響が同疾患の病態と強く関与していることを認識し、本研究においても骨髄微小環境を考慮したDDSの開発を進めている。
はじめに、骨髄の腫瘍細胞に集積する最適なDDSを開発するため、骨髄内の微少血管と腫瘍細胞との関連を検討し、物理化学的特性を考慮した高分子ミセルの選択を検討した。次に、標的指向性を高めるため、発現プロファイルを考慮したうえでの腫瘍細胞表面に結合するリガンド分子のDDSへの組み込みを検討した。また、骨髄内腫瘍細胞に集積するDDSの評価系として、同系移植と異種移植の骨髄腫モデルマウスについて検討した。さらに、骨髄微小環境における免疫細胞とその腫瘍進展への関わりに着目し、免疫細胞と腫瘍細胞との相互作用を増強し抗腫瘍効果を誘導する新しいタイプのDDS製剤として、免疫細胞と腫瘍細胞とを同時に標的とし、NK細胞等のアクセサリー細胞とも結合しうるIgG型二重特異性抗体を作成し、その多発性骨髄腫に対する抗腫瘍効果を評価した。
以上より、当該研究において、多発性骨髄腫の病態とその微小環境に適したDDSとその評価系を研究し、多発性骨髄腫に有用なDDS創薬の開発を目指す基盤構築を進めた。

Research Products

• [Journal Article] Report of the Japan diabetes society/Japanese cancer association joint committee on diabetes and cancer, Second report. (2016)
  • Author(s): Goto A, Noto H, Noda M, Ueki K, Kasuga M, Tajima N, Ohashi K, Sakai R, Tsugane S, Hamajima N, Tajima K, Imai K, Nakagama H.
  • Journal Title: Cancer Science Volume: 107(3) Pages: 369-371
  • DOI: 10.1111/cas.12889.
  • Peer Reviewed / Open Access
• [Journal Article] Report of the Japan Diabetes Society (JDS)/Japanese Cancer Association (JCA) Joint Committee on Diabetes and Cancer, Second Report (2016)
  • Author(s): Goto A, Noto H, Noda M, Ueki K, Kasuga M, Tajima N, Ohashi K, Sakai R, Tsugane S, Hamajima N, Tajima K, Imai K, Nakagama H.
  • Journal Title: Diabeto Int. Volume: 7 Pages: 12-15
  • DOI: 10.1007/s13340-016-0257-z
  • Peer Reviewed
• [Journal Article] Association of Fusobacterium nucleatum with immunity and molecular alterations in colorectal cancer. (2016)
  • Author(s): Nosho K, Sukawa Y, Adachi Y, Ito M, Mitsuhashi K, Kurihara H, Kanno S, Yamamoto I, Ishigami K, Igarashi H, Maruyama R, Imai K, Yamamoto H, Shinomura Y.
  • Journal Title: World J Gastroenterol. Volume: 22 Pages: 557-66
  • DOI: 10.3748/wjg.v22.i2.557
  • Peer Reviewed
• [Journal Article] The relationship between EZH2 expression and microRNA-31 in colorectal cancer and the role in evolution of the serrated pathway. (2016)
  • Author(s): Kurihara H, Maruyama R, Ishiguro K, Kanno S, Yamamoto I, Ishigami K, Mitsuhashi K, Igarashi H, Ito M, Tanuma T, Sukawa Y, Okita K, Hasegawa T, Imai K, Yamamoto H, Shinomura Y, Nosho K.
  • Journal Title: Oncotarget Volume: in press Pages: in press
  • DOI: doi: 10.18632/oncotarget.7260
  • Peer Reviewed
• [Journal Article] HHV-6 encephalitis may complicate the early phase after allogeneic hematopoietic stem cell transplantation: Detection by qualitative multiplex PCR and subsequent quantitative real-time PCR (2016)
  • Author(s): Inazawa N, Hori T, Yamamoto M, Hatakeyama N, Yoto Y, Nojima M, Yasui H, Suzuki N, Shimizu N, Tsutsumi H.
  • Journal Title: J Med Virol Volume: 88 Pages: 319-323
  • DOI: 10.1002/jmv.24340
  • Peer Reviewed
• [Journal Article] Association of Fusobacterium nucleatum with clinical and molecular features in colorectal serrated pathway. (2015)
  • Author(s): Ito M, Kanno S, Nosho K, Sukawa Y, Mitsuhashi K, Kurihara H, Igarashi H, Takahashi T, Tachibana M, Takahashi H, Yoshii S, Takenouchi T, Hasegawa T, Okita K, Hirata K, Maruyama R, Suzuki H, Imai K, Yamamoto H, Shinomura Y.
  • Journal Title: Int J Cancer Volume: 137 Pages: 1258-68
  • DOI: 10.1002/ijc.29488
  • Peer Reviewed
• [Journal Article] Establishment of patient-derived cancer xenografts in immunodeficient NOG mice. (2015)
  • Author(s): Chijiwa T, Kawai K, Noguchi A, Sato H, Hayashi A, Cho H, Shiozawa M, Kishida T, Morinaga S, Yokose T, Katayama M, Takenaka N, Suemizu H, Yamada R, Nakamura Y, Ohtsu T, Takano Y, Imai K, Miyagi Y, Nakamura M.
  • Journal Title: Int J Oncol Volume: 47 Pages: 61-70
  • DOI: 10.3892/ijo.2015.2997.
  • Peer Reviewed / Open Access
• [Journal Article] Epigenetic silencing of NTSR1 is associated with lateral and noninvasive growth of colorectal tumors. (2015)
  • Author(s): Kamimae S, Yamamoto E, Kai M, Niinuma T, Yamano HO, Nojima M, Yoshikawa K, Kimura T, Takagi R, Harada E, Harada T, Maruyama R, Sasaki Y, Tokino T, Shinomura Y, Sugai T, Imai K, Suzuki H.
  • Journal Title: Oncotarget Volume: 6(30) Pages: 29975-90
  • DOI: 10.18632/oncotarget.5034.
  • Peer Reviewed
• [Journal Article] Association of microRNA-31-5p with clinical efficacy of anti-EGFR therapy in patients with metastatic colorectal cancer. (2015)
  • Author(s): Igarashi H, Kurihara H, Mitsuhashi K, Ito M, Okuda H, Kanno S, Naito T, Yoshii S, Takahashi H, Kusumi T, Hasegawa T, Sukawa Y, Adachi Y, Okita K, Hirata K, Imamura Y, Baba Y, Imai K, Suzuki H, Yamamoto H, Nosho K, Shinomura Y.
  • Journal Title: Annals of Surgical Oncology Volume: 22(8) Pages: 2640-2648
  • DOI: 10.1245/s10434-014-4264-7.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Low-frequency IL23R coding variant associated with Crohn’s disease susceptibility in Japanese subjects identified by personal genomics analysis. (2015)
  • Author(s): Onodera K, Arimura Y, Issiki K, Kawakami K, Nagaishi K, Yamashita K, Yamamoto E, Niinuma T, Naishiro Y, Suzuki H, Imai K, Shinomura Y.
  • Journal Title: Plos One Volume: 10(9) Pages: e0137801
  • DOI: 10.1371/journal.pone.0137801
  • Peer Reviewed / Open Access
• [Journal Article] Analysis of the molecular features of rectal carcinoid tumors to identify new biomarkers that predict biological malignancy. (2015)
  • Author(s): Mitsuhashi K, Yamamoto I , Kurihara H, Kanno S, Ito M, Igarashi H, Ishigami K, Sukawa Y, Tachibana M, Takahashi H, Tokino T, Maruyama R, Suzuki H, Imai K, Shinomura Y, Yamamoto H, Nosho K.
  • Journal Title: Oncotarget Volume: 6(26) Pages: 22114-25
  • DOI: 10.18632/oncotarget.4294
  • Peer Reviewed / Open Access
• [Journal Article] Role of interleukin-32 in the mechanism of chronic inflammation in IgG4-related disease and as a predictive biomarker for drug-free remission. (2015)
  • Author(s): Shimizu Y, Yamamoto M, Yajima H, Suzuki C, Naishiro Y, Takahashi H, Imai K, Shinomura Y.
  • Journal Title: Modern Rheumatology Volume: 26(3) Pages: 391-7
  • Peer Reviewed
• [Journal Article] Everyday clinical practice in IgG4-related dacryoadenitis and/or sialadentist: Result from the SMART database. (2015)
  • Author(s): Yamamoto M, Yajima H, Takahashi H, Yokoyama Y, Ishigami K, Shimizu Y, Tabeya T, Suzuki C, Naishiro Y, Takano K, Yamashita K, Hashimoto M, Keira Y, Honda S, Abe T, Suzuki Y, Mukai M, Himi T, Hasegawa T, Imai K, Shinomura Y.
  • Journal Title: Modern Rheumatology Volume: 25(2) Pages: 199-204
  • DOI: 10.3109/14397595.2014.950036
  • Peer Reviewed
• [Presentation] A new approach to the tumor suppression by an anti-erbB-2 trifunctional antibody. Poster Session (2016)
  • Author(s): Kato Y, Hirata H, Tsujisaki M, Matsune T, Adachi Y, Hinoda Y, Sasaki S, Imai K.
  • Organizer: 10th Joint Conference of the American Association for Cancer Research（AACR）and the Japanese Cancer Association（JCA）
  • Place of Presentation: Maui, Hawaii, U.S.A.
  • Year and Date: 2016-02-17 – 2016-02-17
  • Int'l Joint Research
• [Presentation] Serum biomarker screening for BRCTF1-targeted therapy. Poster Session (2016)
  • Author(s): Gunji H, Taniguchi H, Imai K, Kutomi G, Shima H, Miyagi Y, Zembutsu H.
  • Organizer: 10th Joint Conference of the American Association for Cancer Research（AACR）and the Japanese Cancer Association（JCA）
  • Place of Presentation: Maui, Hawaii, U.S.A.
  • Year and Date: 2016-02-17 – 2016-02-17
  • Int'l Joint Research
• [Presentation] 今後の余生を如何にして健康に暮らすか (2015)
  • Author(s): 今井浩三
  • Organizer: 東京いそ会15周年特別講演
  • Place of Presentation: 東京ＩＶＹホール（東京都渋谷区）
  • Year and Date: 2015-12-16 – 2015-12-16
  • Invited
• [Presentation] がんの新規分子診断・治療を目指したトランスレーショナル研究の展開 （口頭） (2015)
  • Author(s): 今井浩三
  • Organizer: 日本癌学会・長與賞受賞記念講演
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-10-10 – 2015-10-10
  • Invited
• [Presentation] がん治療認定医の到達点と今後 (2015)
  • Author(s): 今井浩三
  • Organizer: 朝日がん大賞受賞講演
  • Place of Presentation: 前橋市市民文化会館（群馬県前橋市）
  • Year and Date: 2015-09-03 – 2015-09-03
  • Invited
• [Patent(Industrial Property Rights)] 膜型ムチン様タンパク質の認識とその医療応用 (2016)
  • Inventor(s): 辻祥太郎、今井浩三、ほか
  • Industrial Property Rights Holder: 辻祥太郎、今井浩三、ほか
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 特願2016-25689
  • Filing Date: 2016-02-15