癌特異的分子アネキシンを標的とした泌尿器癌化学療法の開発

2011 Fiscal Year Research-status Report

• Project/Area Number: 23791737
• Research Institution: Hirosaki University
• Principal Investigator: 畠山 真吾 弘前大学, 医学(系)研究科(研究院), 助教 (10400136)
• Project Period (FY): 2011-04-28 – 2015-03-31
• Keywords: 癌化学療法 / アネキシン

Research Abstract

癌化学療法は、副作用の問題が常に課題としてあげられる。癌患者の増加とともに、高効果・低副作用な抗癌剤の開発が求められている。2004年のNatureに固形腫瘍の癌特異的分子としてアネキシンが報告された。アネキシンは癌の新生血管表面に発現する分子で、肺癌、乳癌、前立腺癌など多種の固形腫瘍で発現が確認されている。さらにアネキシンを標的とした治療は、マウスモデルではあるが、治療効果が報告された。しかしその治療法はマウス抗体を用いたものであり、ヒトへの応用はまだ道のりが長いと言わざる負えない。我々はアネキシン結合ぺプチドを同定し、癌特異的化学療法の基礎となる抗癌剤の合成・精製実験を行った。ペプチドの利点は容易に化学合成可能で、各種抗癌剤との組み合わせも可能である点にある。また、大量合成によりコスト削減が期待でき、抗体医薬品のように高価にはならないと考えられる。本研究では、現在臨床応用されている抗癌剤にペプチドを組み合わせ、高効果かつ低副作用な癌特異的抗癌剤の開発を目的としている。H23年：抗癌剤とペプチドの合成：白金系抗癌剤、タキサン系抗癌剤、カンプトテンシンなどとペプチドを化学合成し、抗癌剤を作成する。結果：カンプトテンシン、タキサン系の抗癌剤との合成に成功し、まだ少量ではあるがサンプル採取が可能であった。H24年以降は大量生産系の確立と泌尿器癌モデルマウスの作成と抗癌効果の検討を予定しており、前立腺癌、腎癌等のモデルマウスで抗癌剤の効果や、血液毒性、組織毒性などを検討する予定である。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

カンプトテンシン、タキサン系の抗癌剤との合成に成功し、まだ少量ではあるがサンプル採取が可能であった。今後、実験可能な量まで増産し、泌尿器癌モデルマウスの作成と抗癌効果の検討を行う予定である。

Strategy for Future Research Activity

今後、癌特異的抗癌剤を実験可能な量まで増産し、泌尿器癌モデルマウスの作成と抗癌効果の検討を行う予定である。

Expenditure Plans for the Next FY Research Funding

抗癌剤、ペプチドの購入費、その合成費用、大量合成の費用、細胞培養、マウス実験のための費用に使用する

Research Products

• [Journal Article] MUC1 carrying core 2 O-glycans functions as a molecular shield against NK cell attack, promoting bladder tumor metastasis. (2012)
  • Author(s): Suzuki Y, Sutoh M, Hatakeyama S, Mori K, Yamamoto H, Koie T, Saitoh H, Yamaya K, Funyu T, Habuchi T, Arai Y, Fukuda M, Ohyama C, Tsuboi S.
  • Journal Title: Int J Oncol. Volume: 40 Pages: 1831-1838
  • DOI: 10.3892/ijo.2012.1411.
  • Peer Reviewed
• [Journal Article] Effect of an Oral Adsorbent, AST-120, on Dialysis Initiation and Survival in Patients with Chronic Kidney Disease. (2012)
  • Author(s): Hatakeyama S, Yamamoto H, Okamoto A, Imanishi K, Tokui N, Okamoto T, Suzuki Y, Sugiyama N, Imai A, Kudo S, Yoneyama T, Hashimoto Y, Koie T, Kaminura N, Saitoh H, Funyu T, Ohyama C.
  • Journal Title: Int J Nephrol Volume: 2012 Pages: N/A online only
  • DOI: 10.1155/2012/37612
  • Peer Reviewed
• [Journal Article] Two opposing roles of O-glycans in tumor metastasis. (2012)
  • Author(s): Tsuboi S, Hatakeyama S, Ohyama C, Fukuda M.
  • Journal Title: Trends Mol Med. Volume: 18 Pages: 224-32
  • DOI: 10.1016/j.molmed.2012.02.001
  • Peer Reviewed
• [Journal Article] A switch from conventional twice-daily tacrolimus to once-daily extended-release tacrolimus in stable kidney transplant recipients. (2012)
  • Author(s): Hatakeyama S, Fujita T, Yoneyama T, Yoneyama T, Koie T, Hashimoto Y, Saitoh H, Funyu T, Narumi S,Ohyama C.
  • Journal Title: Transplant Proc. Volume: 44 Pages: 121-3
  • DOI: 10.1016/j.transproceed.2011.11.022
  • Peer Reviewed
• [Journal Article] Genomic profiling of renal cell carcinoma in patients with end-stage renal disease. (2012)
  • Author(s): Inoue T, Hatakeyama S, Ohyama C, Moriyama M, et al.
  • Journal Title: Cancer Sci. Volume: 103 Pages: 569-76.
  • DOI: 10.1111/j.1349-7006.2011.02176.x.
  • Peer Reviewed
• [Journal Article] Clearance and safety of the radiocontrast medium iopamidol in peritoneal dialysis patients. (2012)
  • Author(s): Hatakeyama S, Abe A, Suzuki T, Hashimoto Y, Koie T, Funyu T, Satoh S, Habuchi T, Ohyama C, Matsuo S.
  • Journal Title: Int J Nephrol Volume: 2012 Pages: N/A online only
  • DOI: 10.4061/2011/657051
  • Peer Reviewed
• [Journal Article] Carboplatin-gemcitabine combination chemotherapy upregulates AKR1B10 expression in bladder cancer. (2011)
  • Author(s): Hashimoto Y, Imanishi K, Tokui N, Okamoto T, Okamoto A, Hatakeyama S, Yoneyama T, Koie T, Kamimura N, Ohyama C.
  • Journal Title: Int J Clin Oncol. Volume: in press Pages: N/A
  • DOI: 10.1007/s10147-011-0363-7
  • Peer Reviewed
• [Journal Article] Biochemical outcome of small-volume or insignificant prostate cancer treated with radical prostatectomy in Japanese population. (2011)
  • Author(s): Hashimoto Y, Okamoto A, Imai A, Yoneyama T, Hatakeyama S, Yoneyama T, Koie T, Kaminura N, Ohyama C.
  • Journal Title: Int J Clin Oncol. Volume: 17 Pages: 119-123
  • DOI: 10.1007/s10147-011-0267-6
  • Peer Reviewed
• [Journal Article] Efficacy of SMART Stent Placement for Salvage Angioplasty in Hemodialysis Patients with Recurrent Vascular Access Stenosis. (2011)
  • Author(s): Hatakeyama S, Toikawa T, Okamoto A, Yamamoto H, Imanishi K, Okamoto T, Tokui N, Suzuki Y, Sugiyama N, Imai A, Hashimoto Y, Ohyama C
  • Journal Title: Int J Nephrol. Volume: 2011 Pages: N/A online only
  • DOI: 10.4061/2011/464735
  • Peer Reviewed
• [Journal Article] An aggressive signet ring cell carcinoma of the prostate in a Japanese man. (2011)
  • Author(s): Hashimoto Y, Imanishi K, Okamoto A, Sasaki A, Saitoh H, Wada R, Yamamoto H, Koie T, Ohyama C.
  • Journal Title: Case Rep Oncol. Volume: 4 Pages: 517-520
  • DOI: 10.1159/000334081
  • Peer Reviewed
• [Journal Article] Targeted drug delivery to tumor vasculature by a carbohydrate mimetic peptide. (2011)
  • Author(s): Hatakeyama S, Sugihara K, Shibata TK, Nakayama J, Akama TO, Tamura N, Wong SM, Bobkov AA, Takano Y,Ohyama C, Fukuda M, Fukuda MN.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 108 Pages: 19587-92.
  • DOI: 10.1073/pnas.1105057108
  • Peer Reviewed
• [Journal Article] A novel strategy for evasion of NK cell immunity by tumours expressing core2 O-glycans. (2011)
  • Author(s): Tsuboi S, Sutoh M, Hatakeyama S, Hiraoka N, Habuchi T, Horikawa Y, Hashimoto Y, Yoneyama T, Mori K, Koie T, Nakamura T, Saitoh H, Yamaya K, Funyu T, Fukuda M, Ohyama C.
  • Journal Title: EMBO J Volume: 30 Pages: 3173-85.
  • DOI: 10.1038/emboj.2011.215.
  • Peer Reviewed
• [Journal Article] Requirement for FBP17 in invadopodia formation by invasive bladder tumor cells. (2011)
  • Author(s): Yamamoto H, Sutoh M, Hatakeyama S, Hashimoto Y, Yoneyama T, Koie T, Saitoh H, Yamaya K, Funyu T, Nakamura T, Ohyama C, Tsuboi S.
  • Journal Title: J Urol. Volume: 185 Pages: 1930-8.
  • DOI: 10.1016/j.juro.2010.12.027
  • Peer Reviewed
• [Presentation] Types of urinary diversion have no impact on eGFR decreasing rate (2012)
  • Author(s): Shingo Hatakeyama, Hayato Yamamoto, Shigemasa Kudo, Takahiro Yoneyama, Takuya Koie, Kamimura Noritaka, Chikara Ohyama
  • Organizer: 27th EAU annual congress
  • Place of Presentation: Paris
  • Year and Date: Monday, 27 February 2012
• [Presentation] Incidence and oncologic outcome of renal cell carcinoma (RCC) in hemodialysis (HD) patients detected by annual computed tomography (CT) screening (2012)
  • Author(s): Shingo Hatakeyama, Yuichiro Suzuki2, Hayato Yamamoto, Shigemasa Kudo, Takahiro Yoneyama, Takuya Koie, Noritaka Kamimura, Hisao Saitoh, Tomihisa Funyu, Chikara Ohyama
  • Organizer: 27th EAU annual congress
  • Place of Presentation: Paris
  • Year and Date: Monday, 27 February 2012
• [Presentation] EXPRESSION OF LAMININ-BINDING GLYCANS ON &a-DYSTROGLYCAN CORRELATES WITH TUMOR SUPPRESSOR FUNCTION IN PROSTATE CANCER (2011)
  • Author(s): Shingo Hatakeyama, Xingfeng Bao, Noriko Tokui, et al.
  • Organizer: 106th AUA annual meeting
  • Place of Presentation: Washington DC
  • Year and Date: Sunday, May 15, 2011
• [Presentation] Switching from conventional twice-daily tacrolimus (TAC) to once-daily tacrolimus extended-release (TAC-ER) in stable kidney transplant recipients (2011)
  • Author(s): Shingo Hatakeyama, Takeshi Fujita, Tohru Yoneyama, Takahiro Yoneyama, Takuya Koie, Yasuhiro Hashimoto, Hisao Saitoh, Tomihisa Funyu, Shunji Narumi, Chikara Ohyama
  • Organizer: Congress of Asian Society of Transplantation
  • Place of Presentation: Seoul, Korea
  • Year and Date: Monday, Sept. 2, 2011
• [Presentation] HIGH THROUGH PUT, COMPREHENSIVE AND QUANTITATIVE GLYCOMICS OF WHOLE SERUM GLYCOPROTEINS FOR DIAGNOSIS OF RENAL CELL CARCINOMA (2011)
  • Author(s): Shingo Hatakeyama, Maho Amano, Megumi Tsushima, Hatato Yamamoto, et al.
  • Organizer: 106th AUA annual meeting
  • Place of Presentation: Washington DC
  • Year and Date: Monday, May 16, 2011
• [Presentation] 腎細胞癌における血清糖タンパク糖鎖の網羅的解析 (2011)
  • Author(s): 畠山真吾 、鈴木裕一朗 、杉山尚樹 、米山 徹 、盛 和行 、山本勇人、對馬惠、岡本亜希子 、齋藤久夫、舟生富壽、 天野麻穂 、西村 紳一郎、土谷順彦、羽渕友則 、大山 力
  • Organizer: 99th 日本泌尿器科学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011 – 421