Histological analysis of global DNA methylation in GISTs to overcome their imatinib resistance: integration of diagnostic pathology with GIST model mice towards the development of epigenetic therapy

Research Project

Project/Area Number	25460485
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	Experimental pathology
Research Institution	Hyogo Medical University
Principal Investigator	MATSUDA Ikuo 兵庫医科大学, 医学部, 講師 (50335452)
Project Period (FY)	2013-04-01 – 2017-03-31
Project Status	Completed (Fiscal Year 2016)
Budget Amount *help	¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000) Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000) Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000) Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywords	GIST / イマチニブ / 耐性 / エピゲノム / 5-メチルシトシン / 5-ヒドロキシメチルシトシン / PD-L1 / 血管内皮 / 消化管間質腫瘍 / imatinib / 5-methylcytosine / 5-hydroxymethylcytosine / 薬剤耐性 / モデルマウス / 新規治療薬
Outline of Final Research Achievements	A tyrosine kinase inhibitor imatinib is known to be effective for gastrointestinal stromal tumors (GISTs), a hallmark of which is a constitutive activation of KIT tyrosine kinase by c-kit gene mutation. In order to overcome imatinib resistance in GISTs, imatinib-resistant GISTs were compared with imatinib-naive GISTs as follows in the present investigation. 5-hydroxymethylcytosine was immunohistochemically shown to be globally decreased in imatinib-resistant GISTs as well as in high-risk imatinib-naive GISTs, compared with low-risk imatinib-naive GISTs. On the other hand, in contrast to imatinib-naive GISTs, endothelial induction of PD-L1 was observed in both in and outside of imatinib-resistant GISTs. Imatinib-resistance of GISTs seems to be rather associated with endothelial expression of PD-L1 than global epigenetic change such as decrease in 5hmc. This may be a rational for PD-L1 therapy in order to overcome imatinib resistance of GISTs.