Novel therapeutic strategy in metastatic breast cancer by targeting misfolded protein-transport along microtubules and aggresome formation

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K21388
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General surgery; Applied pharmacology
• Research Institution: Tokyo Medical University
• Principal Investigator: Kazama Hiromi 東京医科大学, 医学部, 助手 (00339350)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 乳がん / アグリソーム / オートファジー / 小胞体ストレス

Outline of Final Research Achievements

We sought to establish a quantitative assay for monitoring ER stress loading. MDA-MB231 cells stably transfected with the ERAI-Venus vector exhibited a strong XBP1 splicing signal in response to ER stress. Using the IncuCyte cell imaging system, we monitored the fluorescence intensity of XBP1-Venus as an ER stress indicator.
Assessment of the XBP1-Venus signal during exposure to various drug combinations revealed that simultaneous inhibition of the proteasome, autophagy, and aggresome formation such as by using bortezomib, clarithromycin, and vorinostat led to more effective ER stress loading and higher cytotoxicity than inhibition of only two components. Thus, rational inhibition of a coordinated intracellular network for coping with the accumulation of misfolded proteins enhance killing of cancer cells subjected to pronounced ER stress loading, that we call “ER stress-loading therapy”.

Free Research Field

腫瘍学

Academic Significance and Societal Importance of the Research Achievements

新薬の開発には莫大な予算とリスクが伴い，前臨床試験から第I～III 相臨床試験を経て承認に至る確率は極めて低い。本研究では既存薬の薬剤コンビネーションによりERストレスを最大限に負荷し、かつ、強力な乳癌細胞に対する殺細胞効果を誘導することを示した。“Drug Re-positioning”の観点からも今後、動物実験で治療効果が検証されれば，臨床試験への移行は比較的容易であり、かつ、難治性乳がんの治療成績の向上に寄与できれば，費用対効果および社会貢献度は極めて高いと考える。