Analyses of anti-tumor activities regarding pazopanib in soft tissue sarcoma

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K10987
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Juntendo University
• Principal Investigator: Kaneko Kazuo 順天堂大学, 医学部, 教授 (50311981)
• Co-Investigator(Kenkyū-buntansha): 末原 義之 順天堂大学, 医学部, 准教授 (70509405) ; 齋藤 剛 順天堂大学, 医学部, 准教授 (80439736)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 軟部肉腫 / pazopanib / GLI1 / 12q13

Outline of Final Research Achievements

In this study, we performed integrate analyses using tumor/normal samples of a advanced STS that achieved a CR to pazopanib to elucidate molecular pathological background of pazopanib response in STSs. The integrate analyses was consisting of a next-generation sequencer (DNA / RNA sequence) and phosphorylation kinase membrane antibody array. As validation study, we verified identified gene alterations and phosphorylated protein expression using the comparative verification cohorts. As the results, we found both characteristic elevated PDGFRB phosphorylation protein of PDGFRB which is the target of pazopanib and specific gene amplification (12q13-14 locus: GLI1, CDK4) in cases that had highly sensitive response to pazopanib. Furthermore, functional analysis also confirmed that characteristic gene amplifications induced the expression of PDGFRB. Based on subsequent validation studies, it was considered that it would contribute to the development of personalized medicine for STSs.

Free Research Field

骨軟部腫瘍

Academic Significance and Societal Importance of the Research Achievements

本研究は、難治性かつ「希少がん」である高悪性軟部肉腫における生命予後の改善に貢献する新規治療法の開発を目的とした。具体的には我々のグループが、Tyrosine kinase (TK)阻害剤であるpazopanib 著効例の高悪性軟部肉腫手術検体より新規発見したキナーゼ遺伝子変異、及びそれらに一致したリン酸化タンパク質の高発現に注目し、大規模コホートによる変異・発現検証及びin vitro, in vivoの機能解析を行った。それら成果は現在まで未知であった難治性軟部肉腫におけるpazopanibの治療奏効・抵抗因子の解明に寄与し、新規個別化治療法の開発に貢献した。