Drug re-positioning screening by using a novel assessment method

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K16548
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Hyogo Medical University (2019); Osaka University (2017-2018)
• Principal Investigator: Noguchi Yuki 兵庫医科大学, 医学部, 病院助手 (30771042)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 腫瘍免疫 / 腫瘍微小環境 / 免疫賦活 / 免疫チェックポイント分子 / ドラッグリポジショニング / テトラサイクリン系抗菌薬 / デメクロサイクリン

Outline of Final Research Achievements

Tumor microenvironment model that has been created using Bispecific T-cell Engager (BiTE) was used for screening old drugs potentially effective on tumor cells. Of 1300 old drugs that have been invented for other diseases except for tumor, one tetracycline antibiotics, demeclocycline (DMC) was found with potential lymphocyte-activation effect. DMC had both quantitative and qualitative abilities against lymphocytes, which means it can proliferate lymphocytes and make them produce much more anti-tumor cytokines, such as interferon gamma. In addition, when DMC was used with a PD-L1 blocker in in vivo mouse model, tumor expansion was significantly suppressed and the proportion of tumor-specific lymphocytes also significantly increased. On top of that, DMC had also an ability to activate tumor infiltrating lymphocytes (TILs) that were extracted from actual tumors of patients with cancer. These results may indicate that DMC enhances the effect of immune checkpoint inhibitors.

Free Research Field

腫瘍免疫

Academic Significance and Societal Importance of the Research Achievements

腫瘍内微小環境は腫瘍に対して免疫抑制状態にあり、腫瘍特異的な免疫反応を再賦活化することで抗腫瘍効果が期待できる。その戦略で開発・実践されている治療法が免疫チェックポイント分子を標的にした生物学的製剤である。これらの薬剤は効果が期待される反面、非常に高価であることから医療経済的な問題が浮上している。そこで免疫チェックポイント分子標的薬に代わり、同じように腫瘍微小環境の腫瘍特異的な免疫反応を賦活化することができる薬剤を、従来他の疾患の治療薬として開発された安価な既存薬の中から探し出し、ドラッグリポジショニングを行うことでより現実的な治療法が可能になるものと考えられる。