Development of targeting cancer therapy against TMEPAI using macrocyclic peptide

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K06682
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47040:Pharmacology-related
• Research Institution: University of Tsukuba
• Principal Investigator: Watanabe Yukihide 筑波大学, 医学医療系, 助教 (40618534)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: がん促進タンパク質 / TMEPAI / 結合環状ペプチド

Outline of Final Research Achievements

TMEPAI is a transmembrane protein which is highly expressed in many types of cancer. The knock-out of TMEPAI in breast cancer cells shows less tumorigenic and lung metastatic abilities, thus TMEPAI potentiates oncogenic properties in cancer cells. Additionally we found that the tumors obtained from TMEPAI knock-out cells reduced the expression of VEGF and IL-8 that are well-known proangiogenic factors.
Moreover, we revealed that TMEPAI is involved in resistance for anti-tumor drugs in triple negative breast cancer cells and the PY motifs in intracellular region of TMEPAI are responsible for the regulation of Wnt signaling pathway. We screened TMEPAI binding macrocyclic peptide and obtained several high affinity binders. Hence we try to apply these macrocyclic peptides for clinical usage.

Free Research Field

腫瘍分子生物学

Academic Significance and Societal Importance of the Research Achievements

乳がんは女性に最も多いがんであり、特にトリプルネガティブ乳がんは分子標的療法の選択肢も少なく、悪性度の高いがんである。TMEPAIはトリプルネガティブ乳がん細胞において、がんを促進することを明らかにしており、TMEPAIの発現を抑えることや、TMEPAIの機能を抑制することで抗腫瘍効果が示唆される。また、TMEPAIの分子メカニズムを明らかにすることで、TMEPAIを標的とした治療や診断法の開発に繋がると考えられる。今回、TMEPAIに結合する特殊環状ペプチドが得られたことで、これらの最適化を行うことで、臨床応用が期待できる。