JP6017367B2 - スクリーニング法 - Google Patents
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Description
a)細胞を
i)薬剤;及び
ii)細胞内タンパク質のレベル又は活性を抑制する化合物
に曝露するステップと、
b)細胞における表現型についてモニターするステップと
を含み、細胞を薬剤単独で処理するときに現れる表現型とは異なる細胞内表現型の出現から、タンパク質又はそれをコードする遺伝子を薬剤感受性と相関するバイオマーカーとして同定する方法が提供される。
i)アクセッション番号NM_002874;NM_002913;NM_002468;NM_002819;NM_005314;NM_002309;NM_002310;NM_002411;NM_002123;NM_002855;NM_016186;NM_000521;NM_002703;NM_002300;NM_002372;NM_016445;及びNM_013352のいずれか1つにおいて列挙される配列を含む、
ii)i)による配列の断片である、
iii)i)又はii)の相補配列を含む、
iv)高度に厳密な条件下で、i)又はii)による核酸分子をハイブリッド形成する、
核酸分子であって、癌などの増殖性疾患、又は細胞の分化若しくは増殖の速度の変化が関与する疾患若しくは病態の診断又は治療に用いる核酸分子を提供する。
i)アクセッション番号NM_002874;NM_002913;NM_002468;NM_002819;NM_005314;NM_002309;NM_002310;NM_002411;NM_002123;NM_002855;NM_016186;NM_000521;NM_002703;NM_002300;NM_002372;NM_016445;及びNM_013352のいずれか1つにおいて列挙される核酸配列がコードするアミノ酸配列を有する、
ii)i)によるタンパク質の断片であって、ただし前記断片が、i)若しくはii)の全長ポリペプチドが有する生物活性を保持する、又はi)若しくはii)のポリペプチドと共通の抗原決定基を有する断片である、
タンパク質であって、癌などの増殖性疾患、又は細胞の分化若しくは増殖の速度の変化が関与する疾患若しくは病態の診断又は治療に用いるタンパク質を提供する。
[実施例]
細胞培養とトランスフェクション
細胞は、10%FCS及び1%ペニシリン/ストレプトマイシン(Gibco社製)を含むDMEM培地(MCF7、U2OS、及びSAOS2細胞)又はRPMI-40培地(A2780細胞)中で培養した。指示通りに、回収前の最終濃度100nMでオリゴフェクタミン(Invitrogen社製)を用いて、U2OS細胞に合成短ヘアピンsiRNA(Dharmacon社製)をトランスフェクトした。
50%エタノール/PBS中、4℃で一晩細胞を固定し、1倍濃度RNAse A及び20ng/mlヨウ化プロピジウムとともに30分間インキュベートした。試料をFACScanフローサイトメーター(BD Bioscience社製)にかけ、CellQuestProソフトウェアを用いて分析した。
マウス異所性受容体(U2OSEcR)を発現するU2OS細胞に、pRetroSuper RNAiライブラリー(Brummelkamp et al, 2002a/b)を感染させた。該ライブラリーの各プールは、ウェル当たり100のsiRNAを含んでいた。細胞の回収に最長72時間をかけることでsiRNAの発現及びノックダウンを可能とした後、細胞をプレートに播種し一晩置いた(プレート当たり細胞40,000個)。次いで、各プレートに、2μl SAHAを加えた(スクリーニング法の前に細胞数とSAHA濃度を決定した)。次いで、18〜30日間にわたり、SAHA及びウイルスライブラリーで共処理したプレートにおいてコロニーが出現するまで、3日ごとにSAHA含有培地を置換した。次いで、コロニーを採取し増殖させ、総ゲノムDNA及び総タンパク質を単離できるようにした(図1)。
溶解緩衝液(100mMトリス[pH8.5]、0.2%SDS、200mM NaCl、及び100μg/mlプロテイナーゼK)を用いて、コロニー細胞からゲノムDNAを分離し、37℃で振とうしながら30分間放置し、DNAを沈殿させた。次いで、溶解物に1容量のイソプロパノールを添加して10mMトリス[pH7.5]中にDNA沈殿物を溶解し、PCRに用いて問題となる遺伝子の同一性の決定を可能にした。PCRは、Expand Long Template PCR System(Roche社製)を用いて実施した。遺伝子挿入物は、以下のプライマーを用いて回収した。pRS順行:5'-CCCTTGGAACCTCCTCGTTCGACC-3'及びpRS逆行:5’-CAGACGTGCTACTTCCATTTGTC-3’。各回のPCRは、1.2%の1倍濃度TBE/アガロースゲルにおいて分析した。次いで、PCR産物の配列を決定し(Lark Technologies社製)、対象となる遺伝子の同定を可能にした。
細胞をPBSで洗浄し、TNN溶解緩衝液(50mMトリス[pH8]、120mM NaCl、0.5% NP-40、1mMジチオスレイトール、及びプロテアーゼ阻害剤)中、4℃で20分間溶解した。抽出物を16,000gで10分間遠心分離し、細胞残屑を除去した。細胞溶解物を標準化し(ブラッドフォード法)、ポンソーS染色で等量のタンパク質添加量を確認した。SDSポリアクリルアミドゲル電気泳動(PAGE,polyacrylamide gel electrophoresis)による変性化の後、Protranニトロセルロース膜に電気転写して総タンパク質を分離し、次いで、抗体により精査した。用いた抗体は、RFC−1、MYD88、LIF、LIFR、及びhnRNPI(サンタクルス、Biotechnology社製)、並びにhHR23B(Biomol社製)であった。増強化学発光試薬(Pierce社製)を用いて、抗体結合を可視化した。
shRNAノックダウンスクリーニング法(Brummelkamp et al, 2002a)は、8,000を超えるヒト遺伝子を標的とするshRNA(pRetroSuperに含まれる)ライブラリーを使用し、各遺伝子につき3つのshRNA表現ベクターを含む。shRNAから産生されるsiRNAは、強力で特異的な遺伝子発現の抑制を誘導し(Brummelkamp et al, 2002a, b)、pRetroSuperを用いるsiRNAの安定的な発現は、長期間にわたる遺伝子発現の抑制を媒介する。これにより、長期のアッセイにおける機能喪失表現型の解析が可能となる。
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Claims (13)
- 増殖性疾患、又は細胞の分化若しくは増殖の速度の変化が関与する疾患を患う患者の、HDAC阻害剤での治療に対する感受性を診断するためのデータを収集する方法であって、前記患者由来の試料における、遺伝子又はその発現産物の、発現若しくは活性レベルを測定するステップと、前記発現又は活性のレベルを基準と比較するステップとを含み、前記発現又は活性のレベルが、前記基準と異なる場合に、基準状態と比べたHDAC阻害剤での治療に対する感受性の変化を示し、前記遺伝子が、hHRAD23B(ヒトrad23B)であり、
前記発現又は活性のレベルを基準と比較した場合に、基準レベルよりも著明に高いレベルのとき、前記患者がHDAC阻害剤での治療に対してより強く感受性であることを示し、基準レベルよりも著明に低いレベルのとき、前記患者がHDAC阻害剤での治療に対して耐性である可能性を示す、方法。 - 発現産物がタンパク質であり、任意で以下のステップを含む、請求項1に記載の方法。
a)リガンド−タンパク質複合体の形成に適切な条件下において、前記タンパク質のリガンドを患者由来の試料に接触させるステップ;及び
b)前記複合体を検出するステップ; - 発現産物が、mRNAである、請求項1に記載の方法。
- 増殖性疾患患者、又は細胞の分化若しくは増殖の速度の変化が関与する疾患患者の、HDAC阻害剤の治療に対する感受性をインビトロで評価するためのデータを収集するための、hHRAD23Bの使用であって、前記患者由来の試料における、hHRAD23B発現又は活性のレベルを基準と比較した場合に、基準レベルよりも著明に高いレベルのとき、前記患者がHDAC阻害剤での治療に対してより強く感受性であることを示し、基準レベルよりも著明に低いレベルのとき、前記患者がHDAC阻害剤での治療に対して耐性である可能性を示す、使用。
- 以下のa)〜c)から選択される核酸分子、又は以下のd)〜f)から選択されるタンパク質を含む、患者における増殖性疾患又は細胞の分化若しくは増殖の速度の変化が関与する疾患の治療剤であって、
前記治療が、前記タンパク質若しくは核酸分子を、HDAC阻害剤と併用した個別、同時、又は逐次投与により投与することを含む、治療剤。
a)配列番号22で示されるヌクレオチド配列を含む核酸分子;
b)a)の相補配列を含む核酸分子;
c)高度に厳密な条件下で、a)の核酸分子とハイブリダイズする核酸分子;
d)hHRAD23Bタンパク質;
e)前記a)の核酸分子の核酸配列にコードされるアミノ酸配列を有するタンパク質;
f)e)のタンパク質の断片であって、ただし前記断片がe)の全長ポリペプチドが有する生物活性を保持する、又はe)のポリペプチドと共通の抗原決定基を有する断片からなるタンパク質; - 患者における増殖性疾患又は細胞の分化若しくは増殖の速度の変化が関与する疾患の、HDAC阻害剤での治療的処置をモニターするためのデータを収集する方法であって、バイオマーカーの発現又は活性レベルを、前記患者由来の試料において一定期間にわたりモニターするステップを含み、前記一定期間における前記発現若しくは活性レベルの、対照レベルに対する変化が、前記疾患又は生理学的状態の退縮を示し、前記一定期間における前記発現若しくは活性レベルを対照レベルと比較した場合に、対照レベルよりも著明に高いレベルのとき、前記患者がHDAC阻害剤での治療に対してより強く感受性であることを示し、対照レベルよりも著明に低いレベルのとき、前記患者がHDAC阻害剤での治療に対して耐性である可能性を示し、
前記バイオマーカーが、(i)以下のa)〜c)から選択される核酸分子、又は(ii)以下のd)〜e)から選択されるタンパク質からなる、前記方法。
a)配列番号22で示されるヌクレオチド配列を含む核酸分子;
b)a)の相補配列を含む核酸分子;
c)高度に厳密な条件下でa)の核酸分子にハイブリダイズする核酸分子;
d)配列番号22で示されるヌクレオチド配列を含む核酸分子の核酸配列にコードされるアミノ酸配列を有するタンパク質;
e)d)のタンパク質の断片であって、ただし前記断片がd)の全長ポリペプチドが有する生物活性を保持する、又はd)のポリペプチドと共通の抗原決定基を有する断片からなるタンパク質; - 増殖性疾患患者、又は細胞の分化若しくは増殖の速度の変化が関与する疾患患者が、HDAC阻害剤での治療に対する感受性があるかどうかの診断に用いるための、以下のa)〜c)から選択されるアレイであって、前記診断が、前記患者から得た試料に対して請求項1〜3のいずれかに記載の方法を実施することを含む、アレイ。
a)核酸分子のそれぞれが、配列番号22で示されるヌクレオチド配列を含む核酸分子の配列に相当するか、配列に相補的であるか、或いは高度に厳密な条件下でハイブリダイズする、少なくとも2つの核酸分子を含むアレイ;
b)各抗体種が、以下のA)〜B)から選択されるタンパク質に免疫特異性を有する、少なくとも2つの異なる種類の抗体種を含むアレイ;
c)以下のA)〜B)から選択される少なくとも2つのタンパク質種を含むアレイ;
A)配列番号22で示されるヌクレオチド配列を含む核酸分子の核酸配列にコードされるアミノ酸配列を有するタンパク質;
B)A)のタンパク質の断片であって、ただし前記断片がA)の全長ポリペプチドが有する生物活性を保持する、又はA)のポリペプチドと共通の抗原決定基を有する断片からなるタンパク質; - 増殖性疾患患者、又は細胞の分化若しくは増殖の速度の変化が関与する疾患患者の治療に用いるためのHDAC阻害剤であって、前記患者が、請求項1〜3のいずれかに記載の方法を用いて投与前にHDAC阻害剤治療に感受性があると同定されていることを特徴とする、HDAC阻害剤。
- 増殖性疾患患者、又は細胞の分化若しくは増殖の速度の変化が関与する疾患患者の治療に用いるためのHDAC阻害剤であって、前記患者が、投与前にhHRAD23Bのレベルが基準レベルよりも著明に高いと同定され、それにより、前記患者は、HDAC阻害剤での治療に対してより強く感受性であることが示されることを特徴とする、HDAC阻害剤。
- 増殖性疾患患者、又は細胞の分化若しくは増殖の速度の変化が関与する疾患患者の、HDAC阻害剤での治療に対する感受性の診断に用いるための、hHRAD23Bタンパク質に特異的に結合する抗体を含むキットであって、前記診断が、前記患者から得た試料に対して請求項1〜3のいずれかに記載の方法を実施することを含む、キット。
- 増殖性疾患患者、又は細胞の分化若しくは増殖の速度の変化が関与する疾患患者の、HDAC阻害剤での治療に対する感受性の診断に用いるための、以下のa)〜c)、又はi)〜ii)を含むキットであって、前記診断が、前記患者から得た試料に対し請求項1〜3のいずれかに記載の方法を実施することを含む、キット。
a)厳密な条件下において、以下のA)〜C)から選択される核酸分子とハイブリダイズする核酸プローブを含む第1の容器;
b)前記核酸分子を増幅するのに有用なプライマーを含む第2の容器;
c)前記プローブ及びプライマーを用いて診断を容易にするための説明書;
i)hHRAD23Bタンパク質に特異的に結合する1又は2以上の抗体;
ii)前記抗体及び前記タンパク質の結合反応の検出に有用な試薬;
A)配列番号22で示されるヌクレオチド配列を含む核酸分子;
B)A)の相補配列を含む核酸分子;
C)高度に厳密な条件下で、A)の核酸分子とハイブリダイズする核酸分子; - 試料が、組織試料である、請求項1〜3のいずれかに記載の方法。
- 試料が、血液、尿、唾液又は特定の組織生検である、請求項1〜3のいずれかに記載の方法。
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