Comparative study of PET hypoxia molecular imaging and tumor vasculature for efficient anticancer drug therapy

• Project/Area Number: 17K11820
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Surgical dentistry
• Research Institution: Hokkaido University
• Principal Investigator: Ohga Noritaka 北海道大学, 歯学研究院, 助教 (40548202)
• Co-Investigator(Kenkyū-buntansha): 北川 善政 北海道大学, 歯学研究院, 教授 (00224957) ; 佐藤 淳 北海道大学, 歯学研究院, 講師 (60319069) ; 山崎 裕 北海道大学, 歯学研究院, 教授 (90250464)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 腫瘍血管新生 / 低酸素 / FMISO-PET / 腫瘍血管密度 / 腫瘍血管の正常化 / 腫脹血管新生 / 未熟血管 / CD31 / 口腔癌 / FDG-PET

Outline of Final Research Achievements

Hypoxia is a common feature of cancer and thus is prognostic factor for many type of cancer. In this retrospective study, immunohistochemistry were performed for CD31 and HIF-1α on 40 OSCCspecimens. Each patient was evaluated by both FMISO-PET before surgery, and the tumor-muscle ratio (TMR) of FMISO-PET were measured. The association between CD31 and HIF1-αexpression and 18F-FMISO uptake(TMR ratio) in the tumor was analyzed statistically. 18F-FMISO uptake in the primary site of OSCC indicates a hypoxic environment with HIF-1α expression.CD31-positive vessel area was increased in the hypoxic tumor compared with that in a non-hypoxic tumor. The tumor vessel in the hypoxic tumor was morphologically more irregular and tortuous than that in the non-hypoxic tumor.We demonstrated a significant relationship between 18F-FMISO TMR and CD31 and HIF1-αexpression in OSCC. In the future, we will perform detailed research on the relationship
between tumor angiogenesis and 18F-FMISO uptake.

Academic Significance and Societal Importance of the Research Achievements

本研究において、FMISO-PET所見から腫瘍血管を「見える化」の一端を実現できたと考えている。個人個人の体内での腫瘍血管の状態を把握することが必要であると考える。
さらに、将来的には低酸素の状態と腫瘍血管の構造状態について実際の臨床に応用できるクライテリアを薬剤到達の観点から検討したい。今後は、北海道大学の口腔外科・口腔内科の口腔癌症例でretrospectiveに検証し、データを蓄積して、抗癌剤使用の有無、stage別での治療反応性、予後を（NC、PR、CR）を検討したい。将来的なクライテリアを構築できるように基礎的データを蓄積し、実際の臨床に応用したいと考えている。

Research Products

• [Journal Article] Imaging modalities for drug-related osteonecrosis of the jaw (3), Positron emission tomography imaging for the diagnosis of medication-related osteonecrosis of the jaw. (2019)
  • Author(s): Kitagawa Y, Ohga N, Asaka T, Sato J, Hata H, Helman J, Tsuboi K, Amizuka N, Kuge Y, Shiga T
  • Journal Title: Jpn Dent Sci Rev Volume: 55 Issue: 1 Pages: 65-70
  • DOI: 10.1016/j.jdsr.2018.12.001
  • NAID: 50014414221
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Imaging modalities for drug-related osteonecrosis of the jaw (3), Positron emission tomography imaging for the diagnosis of medication-related osteonecrosis of the jaw. (2019)
  • Author(s): Kitagawa Y, Ohga N, Asaka T, Sato J, Hata H, Helman J, Tsuboi K, Amizuka N, Kuge Y, Shiga T.
  • Journal Title: Jpn Dent Sci Rev. Volume: 55(1) Pages: 65-70
  • NAID: 50014414221
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Successful conservative treatment of jaw osteonecrosis caused by denosumab in patients with multiple bone metastasis (2018)
  • Author(s): Ohga N, Sato J, Asaka T, Morimoto M, Yamazaki Y, Kitagawa Y.
  • Journal Title: Journal of Oral Science Volume: 60 Issue: 1 Pages: 159-162
  • DOI: 10.2334/josnusd.17-0027
  • NAID: 130006539162
  • ISSN: 1343-4934, 1880-4926
  • Peer Reviewed / Open Access
• [Journal Article] The identification of autoantigens in mucous membrane pemphigoid using immortalized oral mucosal keratinocytes. (2018)
  • Author(s): Kamaguchi M, Iwata H, Miyauchi T, Ujiie H, Ujiie I, Nomura T, Ohga N, Shimizu H, Kitagawa Y.
  • Journal Title: J Oral Pathol Med. Volume: 48(1) Issue: 1 Pages: 1032-1035
  • DOI: 10.1111/jop.12780
  • Peer Reviewed
• [Journal Article] Hypoxic volume evaluated by 18F-fluoromisonidazole positron emission tomography (FMISO-PET) may be a prognostic factor in patients with oral squamous cell carcinoma: preliminary analyses. (2018)
  • Author(s): Sato J, Kitagawa Y, Watanabe S, Asaka T, Ohga N, Hirata K, Shiga T, Satoh A, Tamaki N.
  • Journal Title: Int J Oral Maxillofac Surg Volume: 47(5) Issue: 5 Pages: 553-560
  • DOI: 10.1016/j.ijom.2017.09.007
  • Peer Reviewed / Open Access
• [Journal Article] 18F-Fluoromisonidazole positron emission tomography (FMISO-PET) may reflect hypoxia and cell proliferation activity in oral squamous cell carcinoma. (2017)
  • Author(s): Sato J, Kitagawa Y, Watanabe S, Asaka T, Ohga N, Hirata K, Okamoto S, Shiga T, Shindoh M, Kuge Y, Tamaki N.
  • Journal Title: Oral Surg Oral Med Oral Pathol Oral Radiol Volume: 124(3) Issue: 3 Pages: 261-270
  • DOI: 10.1016/j.oooo.2017.05.506
  • Peer Reviewed / Open Access
• [Presentation] Relationship among hypoxia, FMISO-PET uptake, and tumor angiogenesis in oral squamous cell carcinoma (OSCC) (2019)
  • Author(s): Noritaka Ohga, Jun Sato, Takuya Asaka, Masanobu Shindoh, Yoshimasa Kitagawa
  • Organizer: American Academy of Oral Medicine (AAOM) Annual meeting 2019
  • Int'l Joint Research
• [Presentation] Relationship among hypoxia, 18F-fluoromisonidazole PET uptake, and tumor angiogenesis in oral squamous cell carcinoma (2017)
  • Author(s): Noritaka Ohga, Jun Sato, Takuya Asaka, Yoshimasa Kitagawa
  • Organizer: 日本口腔外科学会
  • Int'l Joint Research / Invited