PETによるアミノ酸トランスポータ標的がん治療のモニタリング法の開発に関する研究

2013 Fiscal Year Research-status Report

• Project/Area Number: 25461801
• Research Category: Grant-in-Aid for Scientific Research (C)
• Research Institution: Gunma University
• Principal Investigator: 織内 昇 群馬大学, 医学(系)研究科(研究院), 客員教授 (40292586)
• Co-Investigator(Kenkyū-buntansha): 富永 英之 福島県立医科大学, 公私立大学の部局等, 准教授 (00393348) ; 大島 康宏 独立行政法人日本原子力研究開発機構, 原子力科学研究部門 量子ビーム応用研究センター, 研究員 (00588676) ; 解良 恭一 群馬大学, 医学(系)研究科(研究院), 講師(Lecture) (40400783)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: アミノ酸トランスポーター / LAT1 / 胆管細胞がん / 胆管がん / 分子標的治療 / mTOR

Research Abstract

LAT1 has vital roles in the growth of cancer via essential amino acid supply for protein synthesis and activation of mTOR signal transduction. Previous studies showed these roles of L-type amino acid transporter 1 (LAT1) in various types of cancer cells. However, pathological significance of LAT1 expression in biliary tract cancer has remained to be elucidated. We conducted in vitro experiment and animal studies to determine biological significance of LAT1 expression and investigate whether LAT1 would be a molecular target of anti-cancer therapy in biliary tract cancer.
In vitro cellular proliferation of human cholangiocarcinoma cell line, HuCCT1, that has higher expression of LAT1 and tumorigenesis in nude mice, was used to see the effect of LAT inhibition by 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH). BCH inhibited [14C]L-leucine uptake in HuCCT1 cells, and significantly decreased number of HuCCT1 cells in a concentration dependent manner.
In vivo anti-tumor effect of LAT inhibition on cholangiocarcinoma was examined using HuCCT1 xenograft in nude mice. Intravenous administration of BCH showed significant delay in the growth of tumor without showing significant changes in the body weight of these mice.
In vitro additive anti-tumor effect of BCH on the gemcitabine (GEM) and 5-fluorouracil (5-FU) was examined. Addition of 10 mM BCH significantly enhanced anti-tumor effect of GEM and 5-FU on HuCCT1 cells.

Current Status of Research Progress

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

Reason

Pathological significance of LAT1 expression in biliary tract cancer was evaluated. In vitro experiments indicated that the inhibition of LAT1 had significant anti-tumor effect on cholangiocarcinoma with acceptable toxicity. LAT1 inhibition showed an additive effect on both GEM and 5-FU therapy. These data suggest that LAT1 would be a target for the cytostatic therapy, and also a candidate of combination chemotherapy with GEM and 5-FU for biliary tract cancer.

Strategy for Future Research Activity

LAT1 has vital roles in the growth of cancer cells via essential amino acid supply for protein synthesis and activation of mTOR signal transduction.
In vitro anti-tumor effect of LAT1 suppression is done by the administration of BCH for human cholangiocarcinoma cell line, HuCCT1 to see the possibility of targeted therapy of LAT inhibition.
In vivo anti-tumor effect of LAT inhibition is done on HuCCT1 xenograft in nude mice. Additional effect of intravenous administration of BCH on conventional gemcitabine and 5-fluorouracil therapy and mTOR inhibitor as well is determined to see the suppression of tumor growth.
Clinical value of LAT1 expression in terms of evaluating biological malignancy and clinical outcome after resection of tumor is assessed by correlating expression status of LAT1 and tumor proliferation determined by Ki-67 labeling index, neovascularization, phosphorylation of proteins for the growth signal transduction. Immunohistochemical staining is done using resected tissue of cholangiocarcinoma to correlate LAT1 expression and other biochemical and pathological parameters as well as clinical markers such as pathological stage, response to therapy, and prognosis.

Research Products

• [Journal Article] Biological evaluation of 3-[18F]fluoro-α-methyl-D-tyrosine (D-[18F]FAMT) as a novel amino acid tracer for positron emission tomography (2013)
  • Author(s): Ohshima Y, Hanaoka H, Tominaga H, Kanai Y, Kaira K, Yamaguchi A, Nagamori S, Oriuchi N, Tsushima Y, Endo K, Ishioka NS
  • Journal Title: Ann Nucl Med Volume: 27 Pages: 314-324
  • DOI: 10.1007/s12149-013-0687-7
  • Peer Reviewed
• [Journal Article] Clinicopathological Significance of L-type Amino Acid Transporter 1 (LAT1) Expression in Patients with Adenoid Cystic Carcinoma. (2013)
  • Author(s): Kaira K, Toyoda M, Shino M, Sakakura K, Takahashi K, Tominaga H, Oriuchi N, Kanai Y, Oyama T, Chikamatsu K
  • Journal Title: Pathol Oncol Res Volume: 19 Pages: 649-656
  • DOI: 10.1007/s12253-013-9624-2
  • Peer Reviewed
• [Journal Article] Diagnostic usefulness of 18F-FAMT PET and L-type amino acid transporter 1 (LAT1) expression in oral squamous cell carcinoma (2013)
  • Author(s): Nobusawa A, Kim M, Kaira K, Miyashita G, Negishi A, Oriuchi N, Higuchi T, Tsushima Y, Kanai Y, Yokoo S, Oyama T
  • Journal Title: Eur J Nucl Med Mol Imaging Volume: 40 Pages: 1692-1700
  • DOI: 10.1007/s00259-013-2477-9
  • Peer Reviewed
• [Journal Article] Clinical significance of L-type amino acid transporter 1 expression as a prognostic marker and potential of new targeting therapy in biliary tract cancer. (2013)
  • Author(s): Kaira K, Sunose Y, Ohshima Y, Ishioka NS, Arakawa K, Ogawa T, Sunaga N, Shimizu K, Tominaga H, Oriuchi N, Itoh H, Nagamori S, Kanai Y, Yamaguchi A, Segawa A, Ide M, Mori M, Oyama T, Takeyoshi I
  • Journal Title: BMC cancer Volume: 13 Pages: 482
  • DOI: 10.1186/1471-2407-13-482
  • Peer Reviewed
• [Presentation] アミノ酸トランスポーターLAT1の臨床病理学的意義ならびに画像マーカーの開発 (2013)
  • Author(s): 織内 昇
  • Organizer: 第51回 日本癌治療学会学術集会
  • Place of Presentation: 京都市
  • Year and Date: 20131024-20131026