2018 Fiscal Year Final Research Report
Selective elimination of tumor clones of primary myelofibrosis based on drug repositioning
| Project/Area Number |
15K07972
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Pharmacology in pharmacy
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| Research Institution | Juntendo University |
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Principal Investigator |
Gotoh Akihiko 順天堂大学, 医学部, 先任准教授 (00297293)
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| Co-Investigator(Kenkyū-buntansha) |
小松 則夫 順天堂大学, 医学部, 教授 (50186798)
宮澤 啓介 東京医科大学, 医学部, 主任教授 (50209897)
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| Research Collaborator |
ARAKI Marito
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| Project Period (FY) |
2015-04-01 – 2019-03-31
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| Keywords | primary myelofibrosis / ruxolitinib / macrolide / thrombopoietin / calreticulin |
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| Outline of Final Research Achievements |
A mutant gene of calreticulin (CALR), which is a major driver mutation for primary myelofibrosis (PMF), was introduced into thrombopoietin (TPO) -dependent cell lines to obtain stable mutant transgenic lines. The mutant transgenic strain acquired TPO-independent growth ability and was considered to reflect the neoplastic character of PMF. Although clarithromycin (CAM) alone does not show a suppressive effect on CALR-mutated cells, the combination with ruxolitinib (RUX) enhanced the cytostatic action of RUX. The combination with RUX by drug repositioning of the macrolides with established safety was considered as a promising option to enhance the clinical effect of RUX.
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| Free Research Field |
血液内科学
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| Academic Significance and Societal Importance of the Research Achievements |
原発性骨髄線維症(PMF)は予後不良な難治性造血器腫瘍である。JAK2 阻害薬ルキソリチニブはPMFに対して脾腫縮小、全身症状改善などの高い臨床効果を示すが腫瘍クローン減少効果は低い。本研究では安全性が確立しているマクロライドのオートファジー阻害活性に注目し、ルキソリチニブとの併用により相乗的にPMFのモデル細胞が抑制されることを示した。この結果はマクロライドのドラッグ・リポジショニングにより、PMFに対して安全性と医療経済効果の両立した分子標的療法を確立する可能性を期待させるものと考えられる。
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