Development of the third generation oncolytic HSV-1 for control of lymph node metastasis and bone invasion in oral cancer

• Project/Area Number: 17K17856
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Surgical dentistry; Tumor therapeutics
• Research Institution: Osaka University
• Principal Investigator: Uchihashi Toshihiro 大阪大学, 歯学部附属病院, 医員 (60757839)
• Research Collaborator: Kogo Mikihiko ; Sugauchi Akinari ; Kurioka Kyoko ; Todo Tomoki ; Ino Yasushi
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: がんウイルス療法 / 口腔癌リンパ節転移 / 抗腫瘍免疫 / 口腔癌のウイルス療法 / ウイルス療法 / 口腔癌 / リンパ節転移 / 遺伝子治療 / 歯学

Outline of Final Research Achievements

In this study, we evaluated the therapeutic efficacy of T-B7-1 or T-mfIL-12, a triple mutated oncolytic HSV-1 expressing soluble murine B7-1, or oncolytic HSV-1 armed with murine interleukin 12 (IL-12)in orthotopic mouse tongue cancer model using KLN205-MUC1 cells. This model reproduces the stepwise development of the disease characterized by local lymph-node metastases followed by lung metastases.
The results suggest that T-B7-1 orT-mfIL-12 more prevents the progression of neck lymph node metastases than T-01, a control virus.

Academic Significance and Societal Importance of the Research Achievements

新たに作成したマウス口腔癌リンパ節転移モデルを用いて、免疫賦活化因子発現型第三世代がん治療用HSV-1は、原発巣に対して極めて有効な治療法であるのみならず、頸部リンパ節転移に対して 有効であることが明らかとなり（特に原発巣に投与した際の頸部微小転移に対して）、これらのウイルスを用いることで、これまで制御困難であった頸部リンパ節転移の制御、および口腔癌患者QOL の保持という口腔扁平上皮癌の治療において非常に重要な効果をもたらすことが期待された。

Research Products

• [Journal Article] Isolation of cancer cells with augmented spheroid-forming capability using a novel tool equipped with removable filter. (2018)
  • Author(s): Fujibayashi E, Yabuta N, Nishikawa Y, Uchihashi T, Miura D, Kurioka K, Tanaka S, Kogo M, Nojima H.
  • Journal Title: Oncotarget Volume: 9 Issue: 74 Pages: 33931-33946
  • DOI: 10.18632/oncotarget.26092
  • Peer Reviewed / Open Access
• [Journal Article] ELAS1 induces apoptotic death in adenocarcinoma DU145 and squamous-cell carcinoma SAS cancer cells, but not in normal KD cells (2017)
  • Author(s): Uchihashi Toshihiro、Ota Kaori、Yabuno Yusuke、Ohno Shouichi、Fukushima Kohshiro、Naito Yoko、Kogo Mikihiko、Yabuta Norikazu、Nojima Hiroshi
  • Journal Title: Oncotarget Volume: 8 Issue: 49 Pages: 85868-85882
  • DOI: 10.18632/oncotarget.20696
  • Peer Reviewed
• [Journal Article] GAK is phosphorylated by c-Src and translocated from the centrosome to chromatin at the end of telophase. (2017)
  • Author(s): Fukushima K, Wang M, Naito Y, Uchihashi T, Kato Y, Mukai S, Yabuta N, Nojima H.
  • Journal Title: Cell Cycle Volume: 16 Issue: 5 Pages: 415-427
  • DOI: 10.1080/15384101.2016.1241916
  • Peer Reviewed
• [Presentation] TGF-β-induced cell cycle arrest is associated with increased migration and metastasis of oral squamous carcinoma cells (2019)
  • Author(s): Kazuki Takahashi, Katarzyna Inoue, Yasuhiro Yoshimatsu, Atsushi Kaida, Kei Takahashi, Shimpei Kubota, Akinari Sugauchi, Toshihiro Uchihashi, Susumu Tanaka, Mikihiko Kogo, Masahiko Miura, Kohei Miyazono, Tetsuro Watabe
  • Organizer: 11th AACR-JCA Joint Conference
  • Int'l Joint Research / Invited
• [Presentation] Highly motile oral squamous carcinoma cells responding to TGF-β are under cell cycle arrest (2019)
  • Author(s): Katarzyna A. Inoue, Kazuki Takahashi, Yasuhiro Yoshimatsu, Akinari Sugauchi, Kei Takahashi, Shimpei. Kubota, Toshihiro Uchihashi, Atsushi Kaida, Susumu Tanaka, Masahiko Miura, Mikihiko Kogo, Kohei Miyazono and Tetsuro Watabe
  • Organizer: Keystone Symposia, Cancer Metastasis:The Role of Metabolism, Immunity and the Microenvironment
  • Int'l Joint Research
• [Presentation] The efficacy of G47Δ in treating mouse tongue cancer models (2018)
  • Author(s): Toshihiro Uchihashi, Akinari Sugauchi, Yasushi Ino, Mikihiko Kogo and Tomoki Todo
  • Organizer: 43rd AOMSI Conference, Chennai, 2018 (1stINDO-JAPAN OMS CONFERENCE）
  • Int'l Joint Research
• [Presentation] Therapeutic efficacy of IL-12 expressing oncolytic HSV-1 for neck lymph node metastases in mouse tongue cancer model (2018)
  • Author(s): Kyoko Kurioka, Toshihiro Uchihashi, Akinari Sugauchi, Hirokazu Nakahara, Yasushi Ino, Mikihiko Kogo and Tomoki Todo
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 口腔扁平上皮癌細胞株SASにおけるEMTとSphere形成能との関連についての検討 (2017)
  • Author(s): 藤林えみ、田中晋、内橋俊大、薮野佑介、古郷幹彦
  • Organizer: 第71回 NPO法人 日本口腔科学学術集会
• [Presentation] LATS and SLUG regulate a malignancy acquired by spiral EMT-MET pathway in oral cancer cells (2017)
  • Author(s): Emi Fujibayashi, Satomi Mukai, Toshihiro Uchihashi, Susumu Tanaka, Mikihiko Kogo and Norikazu Yabuta
  • Organizer: 第76回 日本癌学会学術総会
• [Presentation] Efficacy of oncolytic HSV-1 armed with soluble B7-1 in a mouse model for lymph node metastases of tongue cancer (2017)
  • Author(s): Akinari Sugauchi, Toshihiro Uchihashi, Yasushi Ino, Mikihiko Kogo and Tomoki Todo
  • Organizer: 第76回 日本癌学会学術総会
• [Presentation] 上顎正中過剰埋伏歯抜歯後早期に発生した集合性歯牙種の一例 (2017)
  • Author(s): 内橋俊大、栗岡恭子、須河内昭成、平岡慎一郎、薮野佑介、藤林えみ、相川友直、古郷幹彦
  • Organizer: 第36回日本口腔腫瘍学会総会・学術総会