Drug repositioning of nucleoside reverse transcriptase inhibitor in lung cancer

• Project/Area Number: 16K18464
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor therapeutics
• Research Institution: Kawasaki Medical School
• Principal Investigator: Ochi Nobuaki 川崎医科大学, 医学部, 講師 (80611615)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: Drug repositioning / 化学療法 / NRTI / TDP-1 / SN-38 / abacavir / ドラッグリポジショニング

Outline of Final Research Achievements

We found the relationship between the sensitivity of abacavir and TDP-1 expression in lung cancer. We also revealed the combination of abacavir with SN-38, the active metabolite of irinotecan, showed synergistic effects on the lung cancer cell lines with low TDP-1 expression. Furthermore, TDP-2 expression might affect the sensitivity of those two drugs in some cell lines. The cells intrinsically low TDP-1 expression forcibly introduced TDP-1 gene showed reduced sensitivity to those drugs. Thus, a treatment strategy targeting TDP-1 expression and the combination of abacavir with SN-38 might be a promising treatment approach in lung cancer.

Academic Significance and Societal Importance of the Research Achievements

肺がんを初め多くのがん腫で盛んな分子標的治療薬や、抗PD-1抗体を初めとした免疫チェックポイント阻害剤でもがんの“根治”が困難な現状では、がんのドライバー遺伝子(Oncogene driver)を持たない肺がんに対する治療のみならず、分子標的治療に耐性化した肺がんに対する有効な治療法として既存の化学療法の有効性を、いかに副作用を増強すること無く高めるかが重要であり、副作用プロファイルのまったく異なる薬剤の肺がん治療へのドラッグリポジショニングを検討することは重要である。