JP2017525337A - Ezh2阻害剤への応答についてのバイオマーカー - Google Patents
Ezh2阻害剤への応答についてのバイオマーカー Download PDFInfo
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Abstract
Description
本願は、2014年6月19日に出願された米国仮特許出願第62/014,594号に対する優先権を主張する。この出願の内容は、その全体が本明細書中に参考として援用される。
本発明は、米国国立衛生研究所により授与された助成金番号F31CA180642−01下の政府助成によりなされた。政府は、本発明において一定の権利を有する。
本発明は、EZH2阻害剤が被験体において抗がん効果を生じさせる可能性を評価するのに使用することができるバイオマーカーに関する。したがって、これらのバイオマーカーは、がん患者を処置する方法において使用することができる。
BRCA1関連タンパク質1(BAP1)とは、タンパク質からのユビキチンの除去に関与する、ユビキチンカルボキシ末端ヒドロラーゼである。BAP1は、BRCA1のRINGフィンガードメインを介して、1型乳がん感受性タンパク質(BRCA1)に結合し、腫瘍抑制因子として作用することができる。BAP1は、転写の調節、細胞周期および細胞成長の調節、DNA損傷への応答、ならびにクロマチンダイナミクスに関与する。ゲノムシークエンシング研究は、におけるBAP1の生殖細胞系列変異が、悪性中皮腫、ブドウ膜黒色腫、および皮膚黒色腫を含むがんの危険性の増大を伴う、腫瘍素因症候群(TPDS)と関連しうることを示している。さらなる研究は、肺腺癌および腎細胞癌を含む他のがんと関連する、BAP1生殖細胞系列変異を同定している。悪性中皮腫を有する多くの患者は、自身の疾患で死亡するので、BAP1変異を有する一部の患者の予後は、極めて不良であり、有効な処置が確認されていない。腎細胞癌を有する患者におけるBAP1変異からは、予後不良が予測され、ブドウ膜黒色腫患者におけるBAP1変異からは、高危険性群および転移が予測される。
本発明は、EZH2阻害剤が被験体において抗がん効果を生じさせる可能性を評価するための1または複数のバイオマーカーの使用に関する。それは、少なくとも部分的には、BAP1活性を喪失させると、EZH2の発現および活性の上方調節が結果としてもたらされるという発見に基づく。
明確さのためであり、限定を目的とするものではないが、本発明についての詳細な説明は、以下の小節:
(i)BAP1バイオマーカー;
(ii)EZH2阻害剤;
(iii)がん標的;
(iv)バイオマーカーの検出;
(v)使用方法;および
(vi)キット
へと分けられる。
本明細書で使用される「バイオマーカー」という用語は、被験体における、本明細書でBAP1と表記されるBRCA1関連タンパク質1の活性レベルと関連する、核酸およびタンパク質を含む。
EZH2阻害剤の非限定的な例は、EZH2の発現および/または活性を、阻害および/または低減する、化合物、分子、化学物質、ポリペプチド、タンパク質を含む。EZH2阻害剤のさらなる非限定的な例は、S−アデノシルメチオニン競合的低分子阻害剤を含む。特定の非限定的な実施形態では、EZH2阻害剤は、テトラメチルピペリジニル化合物に由来する。さらなる非限定的な例は、UNC1999、3−デアザネプラノシンA(DZNep)、EI1、EPZ−5676、EPZ−6438、GSK343、EPZ005687、EPZ011989、およびGSK126を含む。
本明細書で開示される主題の対象となりうるがんの非限定的な例は、悪性中皮腫、ブドウ膜黒色腫、腎細胞癌、皮膚黒色腫、肺がん、乳がん、卵巣がん、黒色腫でない皮膚がん、髄膜腫、胆管癌(chlangiocarcinoma)、平滑筋肉腫、神経内分泌腫瘍、膵臓がん、傍神経節腫、悪性線維性組織球腫、骨髄異形成症候群、急性骨髄性白血病、メラノサイトBAP1変異非定型皮内腫瘍(MBAIT)、および膀胱がんを含む。
BAP1核酸バイオマーカーである、EZH2核酸、L3MBTL2核酸、またはSUZ12核酸の発現レベルを、定性的かつ定量的に検出および/または決定するための方法は、従来のqPCRおよびディジタルPCRを含むポリメラーゼ連鎖反応(PCR)、in situハイブリダイゼーション(例えば、蛍光in Situハイブリダイゼーション(「FISH」)であるがこれらに限定されない)、ゲル電気泳動、シークエンシングおよび配列解析、マイクロアレイ解析、ならびに当技術分野で公知の他の技法を含むがこれらに限定されない。
ある特定の非限定的な実施形態では、本発明は、EZH2阻害剤により、がんにおいて、抗がん効果が生じる可能性があるのかどうかを決定する方法であって、BAP1バイオマーカー、例えば、BAP1核酸バイオマーカーおよび/またはBAP1タンパク質バイオマーカーの存在、非存在、および/または発現レベルを決定するステップを含む方法を提供する。BAP1バイオマーカーの存在、非存在、および/または発現レベルを決定するための方法は、上記の5.4節に示されている。処置に適するがんは、上記の5.3節に記載されている。EZH2阻害剤は、上記の5.2節に記載されている。
ある特定の非限定的な実施形態では、本発明は、EZH2阻害剤により、がんにおいて、抗がん効果が生じる可能性があるのかどうかを決定するためのキットであって、前節で示した、BAP1バイオマーカーを検出するための手段を含むキットを提供する。前記キットはさらに、EZH2阻害剤により、がんにおいて、抗がん効果が生じる可能性があるのかどうかを決定するキットの使用について記載する指示もしくは支援材料、および/またはこれについて記載するウェブサイトもしくは刊行物への参照も含みうる。
SET2細胞に、BAP1をターゲティングするshRNAを形質導入して、in vitroにおけるBAP1の発現を低減した。ウェスタンブロットにより検証されるBAP1の発現の低減は、K27におけるヒストン3のトリメチル化(H3K27me3)の増大を結果としてもたらした(図1)。また、図9Aも参照されたい。BaF3細胞におけるBAP1タンパク質の発現を枯渇させ、BAP1の喪失は、ウェスタンブロットにより確認し、ヒストンについての質量分析を実施した。BaF3細胞におけるBAP1のノックダウンは、H3K27me3の増大を明らかにした(図1)。
上記で記載した通り、BAP1タンパク質の発現の喪失は、EZH2により付与される抑制性クロマチンマークであるH3K27me3の増大を引き起こし、in vitroのがん細胞系のシステムにおけるEZH2およびSUZ12の発現を増大させた。EZH2阻害剤は現在、EZH2活性化変異を有するリンパ腫患者において、臨床試験にかけられている。したがって、BAP1変異状態は、EZH2阻害剤による処置に応答しうる患者を同定する一助となる可能性があり、これは、BAP1変異体患者における生存を延長するのに有効でありうる。
プライマー:
ゲノム研究により、異なる悪性腫瘍における、腫瘍抑制因子であるASXL1およびBAP1の体細胞変異が同定された。Drosophila ASXL1の相同体であるAsxと、BAP1の相同体であるCalypsoとは、H2AK119Ubを除去する複合体を形成する(Scheuermannら、2010年)。しかし、BAP1−ASXL1複合体は、BAP1変異体の形質転換において役割を有することが示されていない。骨髄系悪性腫瘍では、ASXL1の不活化変異が最も一般的である(Abdel-Wahabら、2011年;Bejarら、2011年;Gelsi-Boyerら、2009年)のに対し、中皮腫(Bottら、2011年)、腎細胞癌(Pena-Llopisら、2012年)、および転移性ブドウ膜黒色腫(Harbourら、2010年)では、再発性のBAP1変異が一般に観察されていることから、BAP1とASXL1とは、腫瘍の抑制において、顕著に異なる役割を有することが示唆される。これらの変異的プロファイルは、BAP1とASXL1との、差次的な組織特異的発現によっては説明することができない(図5A〜C)。本実施例では、BAP1の喪失が、ASXL1に依存しない形質転換をもたらす機構を同定し、BAP1変異体のがん細胞における治療的脆弱性を同定する。
BAP1とASXL1とは、相互作用して、ヒストンのH2Aリシン119(H2AK119Ub)から、モノユビキチンを除去しうる、ポリコームデユビキチナーゼ複合体を形成する。しかし、BAP1とASXL1とが、顕著に異なるがん型において変異することは、エピジェネティック状態の調節および悪性形質転換における独立の役割と符合する。本実施例では、Bap1の喪失が、トリメチル化ヒストンH3リシン27(H3K27me3)の増大を結果としてもたらし、Ezh2の発現を上昇させ、ポリコーム抑制性複合体2(PRC2)標的の抑制を増強したことが裏付けられる。これらの知見は、Asxl1の喪失について見られる、H3K27me3の低減と対照的である。in vivoにおける、Bap1およびEzh2の条件付き欠失は、Bap1の喪失単独により誘導される骨髄系前駆細胞の拡大を無効化する。Bap1の喪失は、H4K20モノメチル化(H4K20me1)の顕著な減少を結果としてもたらす。H4K20me1メチルトランスフェラーゼであるSETD8の発現が、EZH2の発現を低減し、BAP1変異体細胞の増殖を無効化することは、EZH2の転写の調節におけるH4K20me1の役割と符合する。さらに、BAP1を欠く中皮腫細胞が、EZH2の薬理学的阻害に対して感受性であることから、BAP1変異体の悪性腫瘍に対する新規の治療手法が示唆される。
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Claims (30)
- EZH2阻害剤により、がんにおいて、抗がん効果が生じる可能性があるのかどうかを決定するための方法であって、該がんの1または複数の細胞におけるBAP1バイオマーカーの発現を決定するステップを含み、該BAP1バイオマーカーが、該がんにおいて非存在であるか、または基準対照レベルと比較して低レベルで発現する場合、抗がん効果を生じさせるための治療有効量のEZH2阻害剤を投与する、方法。
- 前記がんが、悪性中皮腫、ブドウ膜黒色腫、腎細胞癌、皮膚黒色腫、肺がん、乳がん、卵巣がん、黒色腫でない皮膚がん、髄膜腫、胆管癌、平滑筋肉腫、神経内分泌腫瘍、膵臓がん、傍神経節腫、悪性線維性組織球腫、メラノサイトBAP1変異非定型皮内腫瘍(MBAIT)、急性骨髄性白血病、骨髄異形成症候群、および膀胱がんからなる群から選択される、請求項1に記載の方法。
- 前記BAP1バイオマーカーの発現を、免疫蛍光法により決定する、請求項1に記載の方法。
- 前記BAP1バイオマーカーの発現を、ウェスタンブロットにより決定する、請求項1に記載の方法。
- 前記BAP1バイオマーカーの発現を、in situハイブリダイゼーションにより決定する、請求項1に記載の方法。
- 前記BAP1バイオマーカーの発現を、ポリメラーゼ連鎖反応により決定する、請求項1に記載の方法。
- 前記BAP1バイオマーカーの発現を、該BAP1バイオマーカーと特異的に結合する試薬を使用することにより検出する、請求項1に記載の方法。
- 前記試薬が、抗体またはその抗原結合性断片である、請求項1に記載の方法。
- 前記がんが、悪性中皮腫である、請求項1に記載の方法。
- 前記がんが、ブドウ膜黒色腫である、請求項1に記載の方法。
- 前記がんが、腎細胞癌である、請求項1に記載の方法。
- 試料中のEZH2の発現レベルを決定するステップをさらに含む、請求項1に記載の方法。
- がんを有する被験体を処置するための方法であって、該被験体から該がんの試料を得るステップと、該試料中において、BAP1バイオマーカーの発現レベル、ならびに/またはEZH2および/もしくはSUZ12の発現レベルを決定するステップとを含み、該BAP1バイオマーカーが非存在であるか、もしくはBAP1の基準対照レベルより低レベルで発現し、かつ/またはEZH2および/もしくはSUZ12の発現が、EZH2の基準対照レベルと比較して増大する場合、治療有効量のEZH2阻害剤による該被験体の処置を開始する、方法。
- 前記がんが、悪性中皮腫である、請求項13に記載の方法。
- 前記がんが、ブドウ膜黒色腫である、請求項13に記載の方法。
- 前記がんが、腎細胞癌である、請求項13に記載の方法。
- 前記BAP1バイオマーカー、SUZ12、およびEZH2の発現を、免疫蛍光法により決定する、請求項13に記載の方法。
- 前記BAP1バイオマーカー、SUZ12、およびEZH2の発現を、ウェスタンブロットにより決定する、請求項13に記載の方法。
- EZH2阻害剤により、がんにおいて、抗がん効果が生じる可能性があるのかどうかを決定するための方法であって、被験体から該がんの試料を得るステップと、該試料中において、BAP1バイオマーカーの発現レベルを決定するステップとを含み、該BAP1バイオマーカーが、該がんにおいて非存在であるか、または基準対照レベルと比較して低レベルで発現する場合、該EZH2阻害剤は、該がんに対して抗がん効果を有する可能性が高い、方法。
- 前記がんが、悪性中皮腫、ブドウ膜黒色腫、腎細胞癌、皮膚黒色腫、肺がん、乳がん、卵巣がん、黒色腫でない皮膚がん、髄膜腫、胆管癌、平滑筋肉腫、神経内分泌腫瘍、膵臓がん、傍神経節腫、悪性線維性組織球腫、メラノサイトBAP1変異非定型皮内腫瘍(MBAIT)、急性骨髄性白血病、骨髄異形成症候群、および膀胱がんからなる群から選択される、請求項19に記載の方法。
- 前記BAP1バイオマーカーが、BAP1タンパク質バイオマーカーである、請求項19に記載の方法。
- 前記BAP1バイオマーカーが、BAP1核酸バイオマーカーである、請求項19に記載の方法。
- 前記BAP1バイオマーカーの発現を、免疫蛍光法により決定する、請求項19に記載の方法。
- 前記BAP1バイオマーカーの発現を、ウェスタンブロットにより決定する、請求項19に記載の方法。
- EZH2阻害剤に対する、患者におけるがんの感受性を予測する方法であって、該患者から該がんの試料を得るステップと、該試料を含む細胞におけるBAP1タンパク質バイオマーカーの発現レベルを決定するステップとを含み、該BAP1バイオマーカーが非存在であるか、または発現レベルが基準対照レベルと比較して低減されている場合、該がんは、EZH2阻害剤に対して感受性であることが予測される、方法。
- 前記がんが、悪性中皮腫、ブドウ膜黒色腫、腎細胞癌、皮膚黒色腫、肺がん、乳がん、卵巣がん、黒色腫でない皮膚がん、髄膜腫、胆管癌、平滑筋肉腫、神経内分泌腫瘍、膵臓がん、傍神経節腫、悪性線維性組織球腫、メラノサイトBAP1変異非定型皮内腫瘍(MBAIT)、急性骨髄性白血病、骨髄異形成症候群、および膀胱がんからなる群から選択される、請求項25に記載の方法。
- EZH2阻害剤により、がんにおいて、抗がん効果が生じる可能性があるのかどうかを決定するためのキットであって、BAP1バイオマーカーを検出するための手段を含むキット。
- BAP1バイオマーカーを検出するための前記手段が、1もしくは複数のパッケージングされたプライマー、プローブ、アレイ/マイクロアレイ、バイオマーカー特異的抗体、および/またはビーズを含む、請求項27に記載のキット。
- BAP1バイオマーカーを検出するための前記手段が、BAP1バイオマーカーを検出するための1もしくは複数の抗体、またはその抗原結合性断片を含む、請求項27に記載のキット。
- EZH2の発現、L3MBTL2の発現、および/またはSUZ12の発現を検出するための1もしくは複数のプライマー、プローブ、アレイ/マイクロアレイ、バイオマーカー特異的抗体、および/またはビーズをさらに含む、請求項27に記載のキット。
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CN106963765B (zh) * | 2017-03-28 | 2020-04-07 | 上海交通大学医学院附属第九人民医院 | Ezh2抑制剂化合物在制备治疗眼部黑色素瘤的药物中的应用 |
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