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唾液腺癌の個別化医療に資するオルガノイドを利用したトランスレーショナルモデルの開発

石川 智彦 東北大学

2021.09.24

概要

背景:唾液腺癌は多彩な組織型を有する希少癌である。高悪性度の唾液腺癌は半数近くで遠隔転移をきたし、全身療法が求められる場面は少なくない。しかし、症例数の少なさ、細胞株やマウスモデルなどの研究資材の乏しさから、有効性の高い確立された全身療法が乏しいことが臨床上の大きな課題である。近年では標準治療の乏しい希少がんに対する治療法として個別の遺伝子プロファイルに基づいた精密医療が治療の可能性を広げているが、唾液腺癌における有効性は明らかとなっていない。また、組織構築を保った三次元がんモデルの一つであるがんオルガノイドは、従来の二次元培養細胞株と比較して生体内の腫瘍と近い性質を持つことが示され、in vitro 薬剤感受性試験に適したモデルとされる。本研究の目的はこれまでにほとんど報告のない多彩な唾液腺癌由来のオルガノイド培養細胞株の樹立、さらにはオルガノイド培養細胞株と網羅的遺伝子解析を組み合わせた個別化医療システムの開発である。

方法:23 例の唾液腺癌と 5 例の唾液腺良性腫瘍を含んだ 28 例を対象とした。患者腫瘍からオルガノイド培養法および二次元培養法による初代培養を行った。同時に腫瘍組織の全エクソン解析を行い、治療標的となりうるドライバー変異を同定した。培養細胞は病理組織学的、分子生物学的な原発腫瘍との相同性を確認した。樹立したオルガノイド細胞株に対して選出した治療薬の効果を検証した。

結果:唾液腺癌症例におけるオルガノイドおよび二次元培養成功率はそれぞれ 69.5% (16/23)、60.8%(14/23)であった。オルガノイドは組織学的・分子生物学的に元の腫瘍の性質を概ね保持していた。一方で、二次元培養細胞では 40%の培養細胞において原発腫瘍で検出されたsomatic mutation が検出されなかった。全エクソン解析ではRAS, NRF2, PI3K, TGFb, WNT, MYC, p53, Hippo, Notch pathway を含んだ複数の幅広い腫瘍関連分子経路に関与する遺伝子異常が検出された。検出された遺伝子異常およびタンパク発現の結果に基づき個々の症例に特異的な分子治療標的を見出し、オルガノイド培養細胞を用いて分子標的治療の効果を検証し得た。

結論:希少癌である様々な組織型の唾液腺癌オルガノイド細胞株の樹立に成功した。オミックス解析に基づく分子標的治療薬の有効性をオルガノイド細胞株上で検証可能であることを示した。本研究は in vitro で個別化精密医療の有効性を検証可能なトランスレーショナルモデルとして、唾液腺癌に対する個別化医療を飛躍的に発展させ得るものである。

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