A study on mechanisms underlying the initial survival of tumor cells against tyrosine kinase inhibitors based on patient-derived tumor models and in vivo real-time imaging
| Project/Area Number |
19K23964
|
|---|
| Research Category |
Grant-in-Aid for Research Activity Start-up
|
| Allocation Type | Multi-year Fund |
|---|
| Review Section |
0902:General internal medicine and related fields
|
|---|
| Research Institution | Nagoya University (2020)
Kyoto University (2019) |
|---|
Principal Investigator |
Tsuji Takahiro 名古屋大学, 医学系研究科, 研究員 (50850046)
|
|---|
| Project Period (FY) |
2019-08-30 – 2021-03-31
|
| Project Status |
Completed (Fiscal Year 2020)
|
| Budget Amount *help |
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
|
|---|
| Keywords | ALK陽性肺癌 / 薬剤耐性 / YAP1 / 治療抵抗性 / 治療初期生存 / 生体イメージング / 転移性脳腫瘍 / 画像解析 / ALK / チロシンキナーゼ / 肺癌 / 初期生存 / アレクチニブ / 分子標的薬 / EML4-ALK陽性肺癌 |
|---|
| Outline of Research at the Start |
本研究は、患者由来肺癌細胞を樹立する技術をと、近年神経科学の分野で発達した生体内イメージング技術を融合させ、分子標的治療の初期に癌細胞の一部が分子標的薬治療から逃避し生存する現象を可視化し、克服治療を開発することを目的とした学際的研究である。これにより、分子標的薬からの逃避を標的とした新たな治療手法を提案し、薬剤により肺癌根治を目指す治療開発が期待できる。
|
| Outline of Final Research Achievements |
Despite the promising clinical efficacy of the second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib in patients with ALK-rearranged lung cancer, some tumor cells survive and eventually relapse, which may be an obstacle to achieving a cure. Limited information is currently available on the mechanisms underlying the initial survival of tumor cells against alectinib. Using patient-derived cell line models, we herein demonstrate that cancer cells survive a treatment with alectinib by activating Yes-associated protein 1 (YAP1), which mediates the expression of the anti-apoptosis factors Mcl-1 and Bcl-xL, and combinatorial inhibition against both YAP1 and ALK provides a longer tumor remission in ALK-rearranged xenografts when compared with alectinib monotherapy. These results suggest that the inhibition of YAP1 is a candidate for combinatorial therapy with ALK inhibitors to achieve complete remission in patients with ALK-rearranged lung cancer.
|
| Academic Significance and Societal Importance of the Research Achievements |
肺癌の薬剤耐性の研究は盛んに行われてきたが、初期生存の研究は少なく、メカニズムは不明である。完全寛解を目指した集中的な治療法は開発されておらず、進行肺癌に対する薬物治療は、数十年前から緩和化学療法と位置づけられている。本研究は、ALK陽性肺癌の根治を目指した多剤併用療法を検討した最初の研究である。この成果をもとに薬剤開発が進めば、薬によって根治を目指した治療を開発できる可能性があり、その社会的な意義は大きい。
|
Report
(3 results)
Research Products
(14 results)
-
-
-
-
-
-
-
-
-
[Presentation] Novel in vivo imaging method to evaluate “Don't eat me” signal of tumor against microglia2020
Author(s)
Takahiro Tsuji, Hiroaki Wake, Mariko Shindo, Koichiro Haruwaka, Hitomi Ajimizu, Masatoshi Yamazoe, Tomoko Funazo, Yuto Yasuda, Hironori Yoshida, Yuichi Sakamori, Young Hak Kim, Hiroaki Ozasa and Toyohiro Hirai
Organizer
AACR annual meeting 2020
Related Report
Int'l Joint Research
-
-
-
[Presentation] YAP1 mediates initial survival of alectinib therapy in ALK-rearranged lung cancer via pro-apoptotic protein regulation2019
Author(s)
Takahiro Tsuji, Hiroaki Ozasa, Wataru Aoki, Shunsuke Aburaya, Tomoko Funazo, Koh Furugaki, Yasushi Yoshimura, Hitomi Ajimizu, Yuto Yasuda, Takashi Nomizo, Yuichi Sakamori, Hironori Yoshida, Mitsuyoshi Ueda, Young Hak Kim and Toyohiro Hirai
Organizer
AACR annual meeting 2019
Related Report
Int'l Joint Research
-
-
