Developing the novel therapeutic strategy with the oligonucleotide therapy against KRAS mutation-positive lung cancer
| Project/Area Number |
19K17653
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 53030:Respiratory medicine-related
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| Research Institution | Hyogo Medical University |
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Principal Investigator |
Mikami Koji 兵庫医科大学, 医学部, 講師 (70567205)
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| Project Period (FY) |
2019-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | KRAS遺伝子変異 / 肺癌 / 核酸治療 / microRNA / KRAS変異 / KRAS / 核酸 / スーパーアパタイト |
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| Outline of Research at the Start |
Driver Oncogeneの2番手でありながら、KRAS変異陽性NSCLCに関しては確立された治療がないのが現状で、MEK阻害薬であるselumetinibを用いた臨床試験でも有効性を示す事はできず、その原因の一つとして、FGFR1を介しAktのリン酸化が促進されるというbypass signalの存在が明らかとなった。miR-4689はMAPK/ERK経路の抑制だけでなく、Aktの蛋白発現そのものを抑制する可能性があるため、MEK阻害薬によって発生したようなAktを介した機序での耐性化は生じにくいと推測され、miR-4689を用いた核酸医療は臨床応用も十分可能と考えられる。
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| Outline of Final Research Achievements |
In our earlier studies, we developed miR-4689 and MIRTX (miR-29b-1-5p complementary sequence) for KRAS mutated colon cancer. In this study, we tried to test whether these microRNA would be effective in inhibiting KRAS mutated non-small cell lung cancer or small cell carcinoma because these diseases are major clinical problems. MIRTX, rather than miR-4689 had a stronger tumor suppressive effect, but it was still not sufficient. RNA sequence analysis indicated many microRNAs that were down-regulated in the KRAS mutated H292 cells as compared with KRAS wild type H292 lung cancer cells. Among them we found that miR-329-3p efficiently inhibited KRAS mutated tumor cells and also small cell carcinoma cells.
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| Academic Significance and Societal Importance of the Research Achievements |
MicroRNAは22塩基程度の短いRNA鎖であり、メッセンジャーR N A(mRNA)の3’UTR（非翻訳領域）に結合して、mRNAの蛋白への翻訳を阻害する。今回、我々が新たに見出したmiR-329-3pは低濃度でKRAS変異を導入したH292細胞の増殖をよく抑制し、更に悪性度の極めて高い肺小細胞癌に対しても著明な抗腫瘍効果を示した。これらの結果は、従来満足のいく治療法がなかった肺癌の治療に大きな希望を与えるものである。
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Report
(3 results)
Research Products
(9 results)
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[Presentation] Efficacy and safety of nivolumab for malignant mesothelioma in the real world.2020
Author(s)
Koji Mikami, Takashi Yokoi, Ryo Takahashi, Eisuke Shibata, Maiko Niki, Yasuhiro Nakajima, Yoshiki Negi, Hirotoshi Ishigaki, Akio Tada, Tomoki Higashiyama, Takao Kamei, Toshiyuki Minami, Kozo Kuribayashi, Takashi Kijima
Organizer
American Society of Clinical Oncology
Related Report
Int'l Joint Research
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[Presentation] Neutrophil-to- lymphocyte ratio as a predictive factor for hyperprogressive disease in NSCLC patients treated with immune checkpoint inhibitor2019
Author(s)
R.Takahashi, E.Shibata, T.Higashiyama, T.kamei, A.Tada, H.Ishigaki, Y.Nakajima, Y.Negi, M.Niki, K.Mikami, T.Minami, T.Yokoi, K.Kuribayashi, T.Kijima
Organizer
ESMO Asia Congress 2019
Related Report
Int'l Joint Research
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