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腎癌のメタボローム解析によるバイオマーカーの確立とチロシンキナーゼ阻害薬耐性獲得機構の解明

佐藤 友紀 東北大学

2020.03.25

概要

(背景)
切除不能および進行腎癌に対し免疫療法が導入され近年、腎癌診療は様変わりしているが、分子標的治療薬であるチロシンキナーゼ阻害薬の重要性は変わっていない。しかし、腎癌細 胞におけるチロシンキナーゼ阻害薬の耐性獲得機構はいまだ十分に解明されていない。

(目的)
メタボロミクスを応用して腎癌の診断と悪性度評価に関わる代謝物を網羅的に同定し、癌代謝の観点から腎癌細胞のチロシンキナーゼ阻害薬の耐性獲得機構を明らかにすること。

(方法)
腎癌の代謝プロファイルを理解するため、手術検体における癌部と非癌部組織を対象とし診断及び予後に寄与する臨床病理悪性度と代謝物の関連を網羅的に解析した。本過程で明らかになった代謝物に対する精密定量測定系を構築しヒト尿検体を用いた腎癌の診断および悪性度評価のバイオマーカーとしての有用性を検証した。更に組織の検討で同定された代謝物はチロシンキナーゼ阻害薬耐性獲得機構にも関連していると予想し、耐性獲得機構の解明を目的に耐性腎癌細胞を in vivo を介して樹立した。本研究ではチロシンキナーゼ阻害薬として sunitinib を用いた。樹立した sunitinib 耐性腎癌細胞中の代謝物を精密定量測定系でコントロール細胞と比較し、耐性獲得に関連する代謝物の解析を行った。

(結果)
腎癌手術検体における癌部と非癌部を比較して腎癌診断に有用な 34 代謝物と悪性度評価に有用な 19 代謝物を同定した。癌診断と悪性度評価の両者に共通して関連する代謝経路は glycolysis (解糖系)、tryptophan 経路、glutathione 経路であった。癌診断に関しては glycerophospholipid、glycoglycerolipid、carnitine 経路、tocopherol 経路が関連し、悪性度に関しては TCA cycle の代謝物、inositol 経路、nucleotide sugar 経路が重要であった。更に同定した代謝物をヒト尿検体から測定する事により診断と悪性度に関する精度の高い予測モデルが構築でき、新たなバイオマーカーとしての臨床応用の可能性を示した。 Sunitinib 耐性腎癌細胞では glutamine の取り込み亢進、解糖系が亢進しており、抗酸化作用の増強が sunitinib 耐性に寄与していた。

(結論)
腎癌の診断と悪性度に関わる代謝物を網羅的に同定し、尿検体の定量測定から、それら代謝物が腎癌診療における有用なバイオマーカーとなり得ることが示された。更に腎癌の sunitinib 耐性獲得には glutamine の取り込みと解糖系によるエネルギー代謝の亢進と抗酸化作用の増強が関与している事を癌代謝の観点から明らかにした。

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