JP2010532668A - Mipol1−etv1遺伝子再編成 - Google Patents
Mipol1−etv1遺伝子再編成 Download PDFInfo
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- JP2010532668A JP2010532668A JP2010516161A JP2010516161A JP2010532668A JP 2010532668 A JP2010532668 A JP 2010532668A JP 2010516161 A JP2010516161 A JP 2010516161A JP 2010516161 A JP2010516161 A JP 2010516161A JP 2010532668 A JP2010532668 A JP 2010532668A
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Abstract
Description
本発明は、それらに限定されるものではないが、癌マーカーを含めた癌の診断、研究、治療のための組成物と方法に関連する。特に、本発明は前立腺癌に対する診断マーカーあるいは臨床上のターゲットとして有用な、反復性のMIPOL1-ETV1遺伝子再編成に関連する。
癌研究は、発癌の原因に関与する遺伝子変化を明らかにする可能性がある。塩基の置換、挿入、欠落、転移や染色体獲得および染色体欠損を含めた、発癌遺伝子や腫瘍抑制遺伝子の活性変化をもたらす、数種類の体細胞突然変異がこれまでに同定されている。癌において、ある種の染色体再編成が発癌の原因となる役割を果たしているという納得できる証拠が存在する(Rowley, Nat Rev Cancer 1: 245 [2001](非特許文献1))。反復性の染色体異常は、白血病、リンパ腫、および肉腫の主要な特徴である。既知の疾患特異的な染色体再編成の1%未満が、はるかに一般的であり、ヒトの癌における罹病率と死亡率の比較的大きな部分を占める上皮性腫瘍(癌腫)に関わり合いがある(Mitelman, Mutant Res 462: 247 [2000](非特許文献2))。造血器腫瘍がしばしば疾患特異性の染色体再編成により特徴付けられる一方、ほとんどの固形腫瘍に非特異的染色体異常の過多が見られる。固形腫瘍の核型の複雑性は、癌の進化や進行の過程で獲得された二次的な変化に起因すると考えられている。
本発明の開示の理解を容易にするために、用語の定義を以下のように規定する。
本明細書に開示される組成物と方法は、前立腺癌における反復性の遺伝子再編成の発見に基づく。これらの組成物と方法は、直接的にまたは間接的にMIPOL1-ETV1遺伝子再編成の検出、あるいはそれをターゲットとする診断への応用、治療法および治療の評価に有用である。
本明細書に開示される反復性の遺伝子再編成は、前立腺癌の徴候を意味する。これらの遺伝子再編成はMIPOL1遺伝物質がETV1遺伝子座位へ挿入される染色体再編成に起因する。これらの反復性の遺伝子再編成は前立腺癌の有用な診断用マーカーであり治療のターゲットである。
本明細書に開示される遺伝子再編成はその結果として、診断や治療への応用に有用な抗体を産生するための免疫原として使用可能な、その断片、誘導体、および類似体を含めた、タンパク質をもたらす。このような抗体は、ポリクローナル、モノクローナル、キメラ型、またはヒト化型であってもよく、単鎖あるいはFab断片でもよく、標識されてもされなくてもよく、これらの全てがよく知られた方法と標準的な実験室操作によって作製できるものである。例えば、Burns編、Immunochemical Protocols(免疫化学のプロトコール)、第3版、Humana Press [2005];HarlowとLane, Antibodies:A Laboratory Manual (抗体:実験室操作法)、Cold Spring Harbor Laboratory [1988];Kozbor等、Immunology Today 4:72 [1983];KohlerとMilstein、Nature 256:495[1975]を参照。
本明細書に開示されたMIPOL1-ETV1遺伝子再編成は、直接的にあるいは間接的に、上記の遺伝子再編成の結果としての遺伝子再編成、あるいは遺伝子再編成の結果として特異的に生成される産生物を検出する、DNA、RNAおよびタンパク質に基づく診断方法を提供する。上記の開示されるMIPOL1-ETV1遺伝子再編成はまた、上記の遺伝子再編成の全てを、あるいは一部を特異的に検出するオリゴヌクレオチドプローブのような診断目的に有用な組成物を提供する。そのような組成物はその形体がキットであってもよい。
MIPOL1-ETV1遺伝子再編成を含む疑いのある生体試料の全てが、本明細書に開示される方法によってテストされ得る。そのような試料は組織(例えば、前立腺生検試料あるいは前立腺切除によって得られる組織)、血液、尿、精液、前立腺分泌物、あるいはそれらの分画(例えば、血漿、血清、尿上清、尿中の細胞ペレットあるいは前立腺細胞)であってもよく、それらは患者あるいはその他の生物学的材料源、例えば、剖検または法医学的材料、から得られてもよい。好ましい実施形態においては、尿試料は、前立腺から前立腺細胞を尿路へ流れさせる注意深い直腸診(DRE)の直後に採取される。
本明細書に開示されるMIPOL1-ETV1遺伝子再編成はゲノムDNAの染色再編成あるいは染色体再編成によって生成されるキメラmRNAとして、例えば、核酸配列決定、核酸ハイブリダイゼーション、そして、核酸増幅のような標準的な実験室方法にたよる、多様なよく知られた核酸技術を使って検出されてもよい。
例証となる核酸配列決定技術の非限定例としては、それらに限定されるものではないが、チェーンターミネーター配列決定法(Sanger)とダイターミネーター配列決定法が含まれる。当業者は、RNAは細胞内で安定性が低くヌクレアーゼにより消化されやすいので、実験においては、配列決定に先立ち、RNAは通常DNAに逆転写されることを認識している。
例証となる核酸ハイブリダイゼーション技術の非限定の例には、それらに限定されることはないが、インサイツハイブリダイゼーション(ISH)、マイクロアレイ、およびサザンあるいはノーザンブロットが含まれる。
幾つかの実施形態においては、遺伝子再編成は蛍光インサイツハイブリダイゼーション(FISH)を用いて検出される。好ましいFISHアッセイは、ヒトゲノム配列決定プロジェクト(Nature 409:953-958[2001]参照)に広く使われ、特異的なBACを含むクローンがどこででも入手可能であるかまたは標準的な実験室操作を使って作製できる細菌人工染色体(BAC)を用いる。ヒトゲノムからの各BACクローンには、それを明瞭に同定する参照名が付けられる。これらの参照名は、相当するGenBankの配列を探したり、販売者からのそのクローンのコピーを注文するために使用される。
マイクロアレイと呼ばれる異なる種類の生物学的アッセイには、それらに限定されるものではないが、以下のものが含まれる:DNAマイクロアレイ(例えば、cDNAマイクロアレイおよびオリゴヌクレオチドマイクロアレイ);タンパク質マイクロアレイ;組織マイクロアレイ;遺伝子導入あるいは細胞マイクロアレイ;化合物マイクロアレイ;そして抗体マイクロアレイ。一般的に遺伝子チップあるいはバイオチップとして知られるDNAマイクロアレイは、同時に何千という遺伝子の発現のプロファイルを調べたり、発現レベルをモニターする目的で、固体表面(例えば、ガラス、プラスチックあるいはシリコンチップ)に付着された顕微鏡的なDNAスポットの整列を集積させたものである。貼り付けられたDNAの分節はプローブとして知られ、その何千もが単一のDNAマイクロアレイに用いられることができる。マイクロアレイは、疾患のある細胞と正常な細胞における遺伝子発現を比較することにより、疾患関連遺伝子を同定するために使用できる。マイクロアレイは、それらに限定されるものではないが、以下のものを含めて多様な技術を使って製作される:ガラススライド上に先細のピンを用いて印を付ける;出来合いのマスクを用いたフォトリソグラフィ;マイクロミラーデバイスを使ったフォトリソグラフィ;インクジェットによる印付け;あるいは微小電極アレイ上での電気化学などによる。
ゲノムDNAとキメラmRNAの染色体再編成は、検出に先立って、あるいは検出と同時に増幅されても良い。核酸増幅技術の例証となる非限定の例には、それらに限定されるものではないが、ポリメラーゼ連鎖反応(PCR)、逆転写ポリメラーゼ連鎖反応(RT-PCR)、転写媒介増幅(TMA)、リガーゼ連鎖反応(LCR)、鎖置換増幅(SDA)、および核酸配列ベース増幅(NASBA)が含まれる。当業者は、増幅技術のあるもの(例えば、PCR)では増幅に先立ってRNAがDNAに逆転写される必要があるが(例えば、RT-PCR)、他の増幅技術は直接RNAを増幅することを認識する(例えば、TMAおよびNASBA)。
非増幅の、または増幅された遺伝子再編成核酸は、従来のいずれの方法によっても検出され得る。例えば、前記の遺伝子再編成は、検出可能なように標識されたプローブとのハイブリダイゼーションと、その結果としてのハイブリッドの測定によって検出され得る。例証となる非制限の検出方法を以下に記載する。
幾つかの実施形態においては、検出アッセイによって生じる生のデータ(例えば、与えられた一つあるいは複数のマーカーの有無、あるいは量)を、臨床医にとって予言的なデータに書き変えるためにコンピューターによる解析プログラムが用いられる。臨床医は、適切な手段のいずれかを用いて、予言的なデータを利用することができる。従って、好適な実施形態の幾つかにおいては、本発明は、遺伝学や分子生物学の訓練を受けていることはなさそうな臨床医が生のデータを理解する必要はない。上記のデータは、最も有用な形式で臨床医に直接、呈示される。そこで、臨床医は、得られた情報を直ちに、患者の医療を最適化するために利用できる。
本明細書に開示される遺伝子再編成はまたインビボ画像解析技術を使用して検出することもでき、それらに限定されるものではないが、それには以下の技術が含まれる;放射性核種画像解析;ポジトロン断層撮影法(PET);コンピューター断層撮影法、X線あるいは核磁気共鳴画像解析法、蛍光検出、および化学発光検出。幾つかの実施形態においては、インビボ画像解析技術は動物体内(例えば、ヒトまたはヒト以外の哺乳動物)における癌のマーカーの存在や発現を可視化するために用いられる。例えば、幾つかの実施形態においては、癌のマーカーに特異的な、標識された抗体を使って癌のマーカーのmRNAあるいはタンパク質が標識される。特異的に結合した標識された抗体は、それらに限定されるものではないが、放射性核種画像解析、ポジトロン断層撮影法、コンピューター断層撮影法、X線あるいは核磁気共鳴画像解析法、蛍光検出、および化学発光検出を含む生体画像解析法によって体内で検出され得る。開示される癌のマーカーに対する抗体の作製法は上述のとおりである。
本明細書に開示される診断方法に用いられる組成物は、それらに限定されるものではないが、プローブ、増幅オリゴヌクレオチド、および抗体を含む。上記組成物は、MIPOL1-ETV1再編成の産物を、好ましくはMIPOL1遺伝物質に挿入されたETV1遺伝物質を検出する。これらの組成物は、限定されるものではないが、次のものを含む:ETV1がMIPOL1遺伝子座位に挿入された連結部(すなわち、遺伝子再編成連結部に及ぶ)とハイブリダイズする配列を含む単一の標識プローブ;第一の増幅オリゴヌクレオチドがMIPOL1とハイブリダイズする配列を含み、第二の増幅オリゴヌクレオチドがETV1とハイブリダイズする配列を含む、一対の増幅オリゴヌクレオチド。しかし、その他の有用な組成物には、第一の標識プローブがMIPOL1とハイブリダイズする配列を含み、第二の標識プローブがETV1とハイブリダイズする配列を含む、一対の標識プローブが含まれる。
幾つかの実施形態においては、前記の開示される組成物と方法は薬物のスクリーニングアッセイに使用される(例えば、癌治療薬をスクリーニングするため)。これらのスクリーニングの方法は、MIPOL1-ETV1遺伝子再編成に関連するものを含む癌マーカーを使用するが、それらの遺伝子再編成に限定されるものではない。例えば、実施形態の一つは、MIPL1-ETV1遺伝子再編成に関連するものを含む癌マーカー遺伝子の発現を変化させる(例えば、減少させる)化合物をスクリーニングしてもよい。スクリーニングされる化合物あるいは薬物は転写を妨げてもよいし(例えば、プロモーター領域との作用によって)、再編成によって生成されるmRNAを妨げてもよいし(例えば、RNA干渉、アンチセンス技術等)、あるいは前記遺伝子再編成の生物学的活性の上流あるいは下流の経路を妨げてもよい。幾つかの実施形態においては、候補化合物は、癌マーカーに対するアンチセンスあるいはRNA干渉作用物質(例えば、オリゴヌクレオチド)である。他の実施形態においては、候補化合物はMIPOL1-ETV1遺伝子再編成に関連する癌マーカー調節分子あるいは発現産物と特異的に結合してその生物学的機能を阻害する抗体あるいは小分子化合物である。
幾つかの実施形態は、癌(例えば、前立腺癌)の治療法を提供する。好適な治療の実施形態は、MIPOL1-ETV1遺伝子再編成に関連するものを含む癌マーカーを、直接的または間接的にターゲットとする。
幾つかの実施形態は、MIPOL1-ETV1遺伝子再編成に関連する癌マーカーの発現をターゲットとする。幾つかの実施形態は、MIPOL1-ETV1遺伝子再編成に関連する癌マーカーをコードする核酸分子の機能を調整する、究極的には発現される癌マーカーの量を調整するために使用するオリゴマーのアンチセンスあるいはRNAi化合物、特にオリゴヌクレオチド(例えば、上記の薬物スクリーニング方法において同定された)を含む。
幾つかの実施形態においては、RNAiはMIPOL1-ETV1遺伝子再編成の発現を阻害するために用いられる。RNAiは、ヒトを含めたほとんどの真核生物における外来性の遺伝子の発現を調整するための、進化的に保存された細胞性防御を象徴する。RNAiは、典型的には二本鎖RNA(dsRNA)によって誘発され、dsRNAに応答して相同性の一本鎖ターゲットRNA配列特異的mRNA分解を起こす。mRNA分解を仲介するのは短い干渉RNA二本鎖(siRNA)であり、それらは、通常は細胞内で長いdsRNAから酵素による切断によって生成される。siRNAは一般的にほぼ21ヌクレオチドの長さ(例えば、21〜23ヌクレオチドの長さ)であり、二つのヌクレオチドの3’オーバーハング(突出)が特徴の塩基対構造を持つ。短いRNA、あるいはRNAiの細胞への導入に続いて、その配列がRISC(RNA誘導サイレンシング複合体)と呼ばれる酵素複合体に届くと考えられている。RISCはターゲットを認識し、エンドヌクレアーゼで切断する。もし、より長いRNA配列が細胞に入ると、RNase IIIの酵素(ダイサー)が長いdsRNAを21〜23ヌクレオチドの二本鎖siRNA断片に変える。幾つかの実施形態においては、RNAiオリゴヌクレオチドは遺伝子再編成の結合領域をターゲットとするようにデザインされる。
他の実施形態においては、MIPOL1-ETV1遺伝子再編成の発現は、MIPOL1-ETV1遺伝子再編成に関連する癌マーカーをコードする一つ以上の核酸と特異的にハイブリダイズするアンチセンス化合物を用いて調整される。オリゴマー化合物とそのターゲットの核酸の特異的なハイブリダイゼーションは、その核酸の正常な機能を妨げる。特異的にハイブリダイズする化合物による、ターゲット核酸の機能の調整は、一般的に「アンチセンス」と呼ばれる。DNAの妨げられる機能には複製と転写が含まれる。RNAの妨げられる機能には、例えば、タンパク質翻訳部位へのRNAの転座、RNAからのタンパク質の翻訳、一つ以上のm RNAを生じるためのスプライシング、RNAに関与するか、あるいは促進される触媒作用、のような生命維持のための全ての機能が含まれる。ターゲット核酸機能に対するそのような干渉はMIPOL1-ETV1遺伝子再編成に関連する癌マーカーの発現調節となる。本明細書に用いられる「調節」という用語は、ある遺伝子の発現の増大(刺激)か、あるいは減少(阻害)を意味する。例えば、発現の阻害は、腫瘍の増殖を潜在的に防ぎ得る。
実施形態は、本明細書に記載されたMIPOL1-ETV1遺伝子再編成に関連する癌マーカーの発現を調節するためのどんな遺伝子操作を用いてもよい。遺伝子操作の実施例としては、それらに限定されるものではないが、遺伝子ノックアウト(染色体から遺伝子再編成を、例えば、遺伝子組み換えによって取り除くような)や、誘導可能なプロモーターが有るまたは無いアンチセンス構築物の発現のような遺伝子操作が含まれる。核酸構築物のインビトロでの送達は、どんな適切な方法を用いて行っても良い。適切な方法とは、核酸構築物を望ましい現象が起こるように(例えば、アンチセンス構築物の発現)、細胞内に核酸構築物を導入するものである。遺伝子治療はまた、インビボで発現されるsiRNAまたはその他の干渉分子を送達するために用いられてもよい(例えば、誘導可能なプロモーター(例えば、アンドロゲン反応性プロモーター)による刺激時)。
幾つかの実施形態は、MIPOL1-ETV1遺伝子再編に関連する癌マーカーを発現する前立腺癌をターゲットとする抗体および/または小分子化合物についてであるか、それらを使用するものである。幾つかの実施形態においては、治療法は、診断結果に基づいて選択され、治療法においての適切な抗体(例えば、モノクローナル、ポリクローナル、または合成された)を用いる。好適な実施形態においては、癌治療に用いられる抗体は、ヒト化された抗体である。抗体をヒト化する方法については、よく知られている(例えば、米国特許番号6,180,370号、5,585,089号、6,054,297号、および5,565,332号を参照とし、これらのそれぞれは参照として本明細書に組み込まれる)。
実施形態は、その変異体や異型体を含む(例えば、トランケーションまたは一塩基多型)、本明細書に記載されるMIPOL1-ETV1遺伝子再編成に同一かあるいはそれを代表する外因性の癌マーカー遺伝子を含む遺伝子改変動物の作製を含む。好ましい実施形態においては、遺伝子改変動物は、野生型の動物に比較して、変化した表現型を示す(例えば、MIPOL1-ETV1遺伝子再編成に関連するマーカーの増大や減少)。そのような表現型の有無を分析する方法には、それらに限定されないが、本明細書に開示されたものが含まれる。好ましい実施形態の幾つかにおいては、遺伝子改変動物はさらに腫瘍の増殖の増加や減少、あるいは癌の徴候を提示する。
以下の実施例は、本明細書に開示されるある好適な実施形態と組成物と方法の態様を説明し例証するために提供されるもので、本発明の請求の範囲を限定するものと解釈されるべきではない。
実施例は、LNCaPおよびMDA-PCa 2B細胞株が、ETV1座位が14q13.3〜14q21.1の位置にある再編成を有することを示す。
この実施例は、14q13.3〜14q21.1の領域が前立腺癌とLNCaP細胞とにおいて協調的に調節されることを示す。
Claims (10)
- 生物学的試料中のMIPOL1-ETV1遺伝子再編成の存在を検出する段階を含む前立腺癌を検出するための方法であって、試料中の該遺伝子再編成の存在が、該試料が由来する個人における前立腺癌を示す、方法。
- MIPOL1-ETV1の遺伝子再編成を検出する段階が、同じゲノム領域にMIPOL1遺伝物質およびETV1遺伝物質を含むゲノムDNAの染色体再編成を検出する段階を含む、請求項1記載の方法。
- ゲノムDNAの染色体再編成を検出する段階が、核酸配列決定技術を使用する、請求項2記載の方法。
- ゲノムDNAの染色体再編成を検出する段階が、核酸ハイブリダイゼーション技術を使用する、請求項2記載の方法。
- ゲノムDNAの染色体再編成を検出する段階が、インサイツハイブリダイゼーション(ISH)、プローブのマイクロアレイへのハイブリダイゼーションの分析、およびサザンブロット分析からなる群から選択される核酸ハイブリダイゼーション技術を使用する、請求項4記載の方法。
- ゲノムDNAの染色体再編成を検出する段階が、核酸増幅法を使用する、請求項2記載の方法。
- 使用される核酸増幅法が、ポリメラーゼ連鎖反応(PCR)、逆転写ポリメラーゼ連鎖反応(RT-PCR)、転写媒介増幅(TMA)、リガーゼ連鎖反応(LCR)、鎖置換増幅(SDA)、および核酸配列ベース増幅(NASBA)からなる群から選択される、請求項6記載の方法。
- 前記試料が、組織、血液、血漿、血清、尿、尿上清、尿中の細胞ペレット、精液、前立腺分泌物および前立腺細胞からなる群から選択される、請求項1記載の方法。
- 前立腺癌に関連するMIPOL1-ETV1遺伝子再編成を検出するための組成物であって、
(a)ETV1遺伝子がMIPOL1遺伝子内に挿入される連結部と特異的にハイブリダイズする配列を含むプローブ、
(b)MIPOL1遺伝子と特異的にハイブリダイズする配列を含む第一のプローブ、およびETV1遺伝子と特異的にハイブリダイズする配列を含む第二のプローブ、または、
(c)MIPOL1遺伝子と特異的にハイブリダイズする配列を含む第一の増幅オリゴヌクレオチド、およびETV1遺伝子と特異的にハイブリダイズする配列を含む第二の増幅オリゴヌクレオチド、および増幅産物を検出するための手段、
のうちの少なくとも一つを含む、組成物。 - (c)における増幅産物を検出するための手段が、プローブ、インターカレート色素、および標識された増幅オリゴヌクレオチドからなる群から選択される、請求項10記載の組成物。
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CA2692793C (en) | 2014-05-20 |
US10167517B2 (en) | 2019-01-01 |
CA2692793A1 (en) | 2009-01-15 |
AU2008275303A1 (en) | 2009-01-15 |
EP2171094A2 (en) | 2010-04-07 |
ATE533861T1 (de) | 2011-12-15 |
WO2009009431A2 (en) | 2009-01-15 |
US9303291B2 (en) | 2016-04-05 |
US20160208343A1 (en) | 2016-07-21 |
ES2376509T3 (es) | 2012-03-14 |
EP2171094B1 (en) | 2011-11-16 |
US20170327901A1 (en) | 2017-11-16 |
AU2008275303B2 (en) | 2012-05-03 |
US20110028336A1 (en) | 2011-02-03 |
WO2009009431A3 (en) | 2009-04-02 |
JP5433572B2 (ja) | 2014-03-05 |
US9719143B2 (en) | 2017-08-01 |
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