New strategy for oral cancer based on molecular imaging reflecting therapeutic resistance

• Project/Area Number: 16H05536
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Surgical dentistry
• Research Institution: Hokkaido University
• Principal Investigator: KITAGAWA Yoshimasa 北海道大学, 歯学研究院, 教授 (00224957)
• Co-Investigator(Kenkyū-buntansha): 竹内 康人 北海道大学, 遺伝子病制御研究所, 特別研究員(PD) (10735187) ; 大賀 則孝 北海道大学, 歯学研究院, 助教 (40548202) ; 佐藤 淳 北海道大学, 歯学研究院, 講師 (60319069) ; 久下 裕司 北海道大学, アイソトープ総合センター, 教授 (70321958) ; 犬伏 正幸 川崎医科大学, 医学部, 准教授 (70399830) ; 玉木 長良 北海道大学, 医学研究科, 特任教授 (30171888)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2018: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥7,670,000 (Direct Cost: ¥5,900,000、Indirect Cost: ¥1,770,000)
• Keywords: 分子イメージング / 遺伝子イメージング / 低酸素 / 遺伝子応答 / PET / 治療抵抗性 / 化学療法 / 頭頸部癌 / FMISO / 口腔がん / 臨床研究 / 動物モデル / 核医学(PET) / 核医学 (PET) / FIMISO / 核医学（PET） / 核医学（PET)

Outline of Final Research Achievements

Hypoxia is a negative prognostic factor due to its association with an aggressiveness and therapeutic resistance. HIF-1/HRE pathway is a promising target for the imaging and the treatment of intractable malignancy (HIF-1; hypoxia-inducible factor 1, HRE; hypoxia responsive element).　The tumor uptake level of hypoxia-targeted PET tracers reflected the gene activation level of HRE, which eventually conferred resistance to anti-cancer therapies.
FMISO-PET and FDG-PET were performed in patients with oral SCC (OSCC) to elucidate the correlation between PET uptake and various parameters. FMISO uptake was an independent significant predictor of response to preoperative chemotherapy.　hypoxic volume (HV) correlated significantly with both disease-free survival and loco-regional recurrence. Tumor HV measured by FMISO-PET may predict outcomes in patients with OSCC.

Academic Significance and Societal Importance of the Research Achievements

腫瘍内環境における低酸素は多くの固形癌の強力な予後因子とされているが、低酸素状態の可視化は極めて困難であった。われわれは低酸素状態で遺伝子応答する癌細胞株を樹立し、動物実験でイメージングに成功した。さらに低酸素分子イメージングとしてFMISO-PETを口腔癌に臨床応用した。FMISO-PETの集積と組織中のHIF-1αの発現が有意に関連していることを世界で初めて明らかにした。術前化学療法の効果の予測、増殖能との関係、低酸素容積と予後との関連も見いだした。

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] 特集 薬剤関連顎骨壊死の画像診断up to date 薬剤関連顎骨壊死のPET検査 (2018)
  • Author(s): 北川善政、浅香卓哉、佐藤 淳 秦 浩信、坪井香奈子、網塚憲生、久下裕司、志賀 哲
  • Journal Title: 臨床放射線 Volume: 63 Issue: 10 Pages: 1071-1081
  • DOI: 10.18888/rp.0000000575
  • ISSN: 0009-9252
  • Year and Date: 2018-10-10
  • 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] Clinical possibility of baseline FDG-PET SUVmax as a prognostic factor in patients with head and neck non-Hodgkin's lymphoma: a preliminary study. (2018)
  • Author(s): Yoshikawa K, Onodera-Kyan M, Kitagawa Y, Satoh A, Sato J, Kitamura T, Shiga T, Watanabe S
  • Journal Title: Journal of Oral and Maxillofacial Surgery, Medicine and Pathology (JOMSMP) Volume: 30 Pages: 319-323
  • Peer Reviewed
• [Journal Article] Clinical possibility of baseline FDG-PET SUVmax as a prognostic factor in patients with head and neck non-Hodgkin's lymphoma: a preliminary study. (2018)
  • Author(s): 3.Yoshikawa K, Onodera-Kyan M, Kitagawa Y, Satoh A, Sato J, Kitamura T, Shiga T, Watanabe S.
  • Journal Title: Journal of Oral and Maxillofacial Surgery, Medicine and Pathology (JOMSMP) Volume: 30
  • Peer Reviewed
• [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
• [Journal Article] Unusual maxillary osteoblastic and osteolytic lesions presenting as an initial manifestation of childhood acute myeloid leukemia: A case report. (2017)
  • Author(s): Shimizu R, Ohga N, Miyakoshi M, Asaka T, Sato J, Kitagawa Y.
  • Journal Title: Quintessence Int. Volume: 48 Pages: 149-153
  • Peer Reviewed
• [Journal Article] Dynamic PET evaluation of elevated FLT level after sorafenib treatment in mice bearing human renal cell carcinoma xenograft. (2016)
  • Author(s): Ukon N, Zhao S, Yu W, Shimizu Y, Nishijima KI, Kubo N, Kitagawa Y, Tamaki N, Higashikawa K, Yasui H, Kuge Y
  • Journal Title: EJNMMI Res Volume: 6(1) Issue: 1 Pages: 90-90
  • DOI: 10.1186/s13550-016-0246-z
  • NAID: 120005972935
  • Peer Reviewed
• [Journal Article] Unusual maxillary osteoblastic and osteolytic lesions presenting as an initial manifestation of childhood acute myeloid leukemia: A case report. (2016)
  • Author(s): Shimizu R, Ohga N, Miyakoshi M, Asaka T, Sato J, Kitagawa Y
  • Journal Title: Quintessence Int Volume: 48(2) Pages: 149-153
  • Peer Reviewed
• [Journal Article] Platelet-rich fibrin may reduce the risk of delayed recovery in tooth-extracted patients undergoing oral bisphosphonate therapy: a trial study. (2016)
  • Author(s): Asaka T, Ohga N, Yamazaki Y, Sato J, Satoh C, Kitagawa Y
  • Journal Title: Clin Oral Investig Volume: epub Issue: 7 Pages: 1-8
  • DOI: 10.1007/s00784-016-2004-z
  • Peer Reviewed / Open Access
• [Journal Article] Changes in tumor oxygen state after sorafenib therapy evaluated by 18F-fluoromisonidazole hypoxia imaging of renal cell carcinoma xenograft (2016)
  • Author(s): Wenwen Yu, Songji Zhao, Yan Zhao, Chowdhury Nusrat Fatema, Masahiro Murakami, Ken-ichi Nishijima, Yoshimasa Kitagawa, Nagara Tamaki, and Yuji Kuge
  • Journal Title: Oncology Letters Volume: epub
  • Peer Reviewed
• [Journal Article] Use of FDG-PET to detect a chronic odontogenic infection as a possible source of the brain abscess. (2016)
  • Author(s): 2)Sato J, Kuroshima T, Wada M, Satoh A, Watanabe S, Okamoto S, Shiga T, Tamaki N, Kitagawa Y
  • Journal Title: Odontology Volume: 104 Issue: 2 Pages: 239-243
  • DOI: 10.1007/s10266-015-0218-1
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The reoxygenation of hypoxia and the reduction of glucose metabolism in head and neck cancer by fractionated radiotherapy with intensity-modulated radiation therapy. (2016)
  • Author(s): Okamoto S, Shiga T, Yasuda K, Watanabe S, Hirata K, Nishijima KI, Magota K, Kasai K, Onimaru R, Tuchiya K, Kuge Y, Shirato H, Tamaki N.
  • Journal Title: Eur J Nucl Med Mol Imaging Volume: 43(12) Issue: 12 Pages: 2147-2154
  • DOI: 10.1007/s00259-016-3431-4
  • Peer Reviewed
• [Presentation] 頭頸部非ホジキンリンパ腫における治療前のFDG-PETおよび血清パラメーターの予後不良因子としての有用性 (2019)
  • Author(s): 吉川和人、佐藤 淳、佐藤 明、小野寺麻記子、北村哲也、北川善政、志賀 哲、渡邊史郎
  • Organizer: 第45回 北海道頭頸部腫瘍研究会
• [Presentation] MRONJ 最近の動向と医科歯科連携 (2019)
  • Author(s): 北川善政
  • Organizer: 日本歯科放射線学会 第38 回関西・九州合同地方会
  • Invited
• [Presentation] FDG-PET and 3-phase bone scintigraphy to monitor the activity of MRONJ (2019)
  • Author(s): Yoshimasa Kitagawa
  • Organizer: 60th Anniversary of KAOMS
  • Int'l Joint Research / Invited
• [Presentation] 頭頸部非ホジキンリンパ腫における治療前のFDG-PETおよび血清パラメーターの予後不良因子としての有用性 (2018)
  • Author(s): 吉川和人、佐藤 淳、佐藤 明、小野寺麻記子、北村哲也、北川善政
  • Organizer: 第63回 日本口腔外科学会学術大会・総会
• [Presentation] Prognostic value of MET-PET in oral cancer (2017)
  • Author(s): Chowdhury Nusrat Fatema, Kuroshima Takeshi, Asaka Takuya, Abe Takahiro, Sato Jun, Shiga Tohru, Kuge Yuji, Tamaki Nagara, Kitagawa, Yoshimasa
  • Organizer: The 64th Annual Meeting of the Society of Nuclear Medicine and Molecular Imaging
  • Int'l Joint Research
• [Presentation] 18F-Fluoromisonidazole positron emission tomography (FMISO-PET) may better reflect hypoxia and cell proliferation activity in oral squamous cell carcinoma than 18F-fluoro-2-deoxyglucose (FDG)-PET: third study. (2017)
  • Author(s): Sato Jun, Kitagawa Yoshimasa, Watanabe Shiro, Okamoto Shozo, Ohga, Noritaka, Asaka Takuya, Miyakoshi Masaaki, Hirata Kenji, Shiga Tohru, Kuge Yuji, Shindoh Masanobu, Tamaki Nagara
  • Organizer: The 64th Annual Meeting of the Society of Nuclear Medicine and Molecular Imaging
  • Int'l Joint Research
• [Presentation] 北大歯科における核医学を用いた臨床研究 (2017)
  • Author(s): 佐藤 淳
  • Organizer: 第52回 日本核医学会 中国・四国地方会・ランチョンセミナ－
  • Invited
• [Presentation] 顎口腔領域におけるPET診断と治療への応用 (2017)
  • Author(s): 北川善政
  • Organizer: 日本歯科放射線学会第58回学術大会
  • Invited
• [Presentation] 薬剤関連顎骨壊死 のＰＥＴ検査 (2017)
  • Author(s): 北川善政
  • Organizer: 第57回日本核医学会学術総会 口腔顎顔面核医学フォーラム
  • Invited
• [Presentation] 口腔扁平上皮癌における低酸素容積: hypoxic volumeは術後の予後予測因子になりえる (2016)
  • Author(s): 佐藤 淳、大賀則孝、浅香卓哉、宮腰昌明、吉川和人、佐藤千晴、佐藤 明、北川善政
  • Organizer: 第61日本口腔外科学会総会・学術大会
  • Place of Presentation: 幕張メッセ（千葉県・千葉市）
  • Year and Date: 2016-11-25
• [Presentation] Metabolic activityを用いた顎骨骨髄炎に対する新規定量的評価法の確立 (2016)
  • Author(s): 浅香卓哉、佐藤淳、秦浩信、宮腰昌明、佐藤明、北川善政
  • Organizer: 第61日本口腔外科学会総会・学術大会
  • Place of Presentation: 幕張メッセ（千葉県・千葉市）
  • Year and Date: 2016-11-25
• [Presentation] Usefulness of MET-PET in oral cancer (2016)
  • Author(s): Chowdhury Nusrat Fatema, Takeshi Kuroshima, Takuya Asaka, Takahiro Abe, Jun Sato, Yoshimasa Kitagawa
  • Organizer: 61st Congress of the Japanese Society of Oral and Maxillofacial Surgeons
  • Place of Presentation: 幕張メッセ（千葉県・千葉市）
  • Year and Date: 2016-11-25
• [Presentation] Relationships between FMISO- and FDG-PET parameters including hypoxic volume of the tumor and prognosis in patients with oral squamous cell carcinoma after surgery (2016)
  • Author(s): Sato, Jun, Kitagawa, Yoshimasa, Watanabe, Shiro, Kenji Hirata, Okamoto, Shozo, Noritaka, Ohga, Asaka, Takuya, Miyakoshi, Masaaki, Hata, Hironobu, Shiga Tohru, Shindoh Masanobu, Tamaki Nagara
  • Organizer: Annual Congress of the European Association of Nuclear Medicine
  • Place of Presentation: Barcelona (Spain)
  • Year and Date: 2016-10-18
  • Int'l Joint Research
• [Presentation] MRONJに対する高気圧酸素療法(HBO)の応用とFDG-PETによる評価 (2016)
  • Author(s): 北川善政
  • Organizer: 第70回日本口腔科学会総会
  • Place of Presentation: 福岡国際会議場（福岡県・福岡市）
  • Invited