JP2016518815A - 転移性がんの診断、予後、および処置の方法 - Google Patents
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Abstract
Description
本発明は、がん、特に乳がん、結腸がん、肺がん、腎臓がん、または甲状腺がんに罹患した被験体が転移を生じる可能性を決定する方法、さらに、がん、特に乳がん、結腸がん、肺がん、腎臓がん、または甲状腺がんに罹患した被験体のための個別対応の治療を生み出す方法に関する。かかる方法は、発現がc−MAF遺伝子発現に関連する一群の遺伝子の発現レベルを決定する工程からなる。本発明はまた、転移性がん、特に乳がん、結腸がん、肺がん、腎臓がん、または甲状腺がんの処置および/または予防におけるPTHLHインヒビターおよびPODXLインヒビターならびにRERGアクチベーターの使用を含む。
乳がんは、全世界で2番目に一般的ながんタイプであり(10.4%;肺がんに次ぐ)、且つ5番目に一般的ながんによる死因である(肺がん、胃がん、肝臓がん、および結腸がんに次ぐ)。乳がんは女性における最も一般的な死因でしょうか?2005年、乳がんによる全世界の死亡者数は502,000人であった(がん関連死の7%;全死亡率のほぼ1%)。世界的な症例数は、1970年代以来有意に増加しており、この現象の一部は西洋の現代的な生活様式による。
本発明者らは、c−MAF遺伝子発現の変化の結果として発現が乳房腫瘍サンプル中で増加または減少する遺伝子群を同定した。機能獲得型実験および相関する臨床データを使用して、本発明者らは、これらの遺伝子、特に、発現がc−MAFの発現に逆に関連するRERG遺伝子ならびに発現がc−MAF発現に直接関連するPTHLH遺伝子およびPODXL遺伝子(ER+乳がんの骨転移の予後マーカーなど)の役割を確認した。
(i)原発性がん腫瘍サンプル中、特に乳がんサンプル中の候補遺伝子およびc−MAF遺伝子の発現レベルを定義する工程、および
(ii)c−MAF遺伝子発現の調整に応答したがん細胞集団、特に乳房細胞集団中の前記候補遺伝子の発現レベルの変化を決定する工程
を含み、
ここで、前記遺伝子の発現レベルが原発性がん腫瘍サンプル中、特に乳がんサンプル中のc−MAF発現に関して統計的に有意であり、c−MAF遺伝子発現の調整に応答した発現の変化が前記遺伝子のレベルの変化に関して統計的に有意である場合、前記遺伝子が、転移を生ずる被験体の性向についてのマーカーであることを示す、方法に関する。
一般的な表現および用語の定義
「c−MAFインヒビター」は、本発明中で使用する場合、c−MAF遺伝子の発現を部分的または完全に阻害すること(前記遺伝子の発現が引き起こされることからの予防(c−MAF遺伝子の転写の破壊および/またはc−MAF遺伝子発現に由来するmRNAの翻訳の遮断)およびc−MAFタンパク質活性の直接的阻害の両方)が可能な任意の分子をいう。c−MAF遺伝子発現インヒビターを、国際特許出願WO2005/046731号に例示の推定インヒビターがc−MAFのin vitroでの細胞増殖促進能力を遮断する能力に基づいた、WO2008098351号に記載のc−MAFを発現する細胞中でサイクリン−D2プロモーターまたはc−MAF応答領域(MAREまたはc−MAF応答エレメント)を含むプロモーターの調節下で推定インヒビターがレポーター遺伝子の転写能力を遮断する能力に基づいた、またはUS2009048117A号に記載のNFATc2およびc−MAFを発現する細胞中でPMA/イオノマイシンでの刺激に応答したIL−4プロモーターの調節下で推定インヒビターが遺伝子の発現を遮断する能力に基づいた方法を使用して同定することができる。
−病期0:腸最内層中の初期のがん
−病期1:腸内層中のがん
−病期2:結腸筋肉壁を介して進行したがん
−病期3:リンパ節に進行したがん
−病期4:がんが他の器官に進行している。
・NX:隣接リンパ節転移の評価不可能。N0:がんがリンパ節へ広がっていない。N1:がんが1〜3つの腋窩リンパ節または1つの内胸リンパ節へ広がっている。N2:がんが4〜9つの腋窩リンパ節または複数の内胸リンパ節へ広がっている。N3:以下のうちの1つを適用する:
・10またはそれを超える腋窩リンパ節にがんが広がっているか、鎖骨直下のリンパ節にがんが広がっているか、鎖骨上部のリンパ節にがんが広がっているか、腋窩リンパ節ががんに侵され、且つ内乳房リンパ節に広がっているか、4つまたはそれを超える腋窩リンパ節ががんに侵され、且つ内胸リンパ節生検またはセンチネルリンパ節生検で最少量のがんが見いだされる。
本発明者らは、発現がc−MAF発現と正または負に相関する遺伝子の群を同定した。具体的には、本発明者らは、以下の理由によって特徴づけられる一連の遺伝子を同定した(i)原発性腫瘍中のそれらの発現がMAF発現と有意に相関すること、および(ii)MCF7細胞内でのそれらの発現がMAFを発現するMCF7から誘導された、骨に高度に転移した細胞中のc−MAF過剰発現(長いアイソフォームまたは短いアイソフォーム)またはc−MAFサイレンシングによって改変されること。これらの条件を満たす遺伝子は、c−MAFによって媒介される骨転移プログラムのメンバーであると考えられる。これらの遺伝子を、表1(c−MAFプログラムによって増加する遺伝子)および表2(MAFプログラムによって抑制される遺伝子)に示す。機能獲得型実験および臨床相関データを使用して、本発明者らは、ER+乳がんの骨転移過程の原因となる標的遺伝子としての、およびc−MAFによって媒介される骨転移プログラムの一部としてのPTHLH、PODXL、およびRERGの役割を機能的に確認した。
技術の現状が公知である場合、乳がん、結腸がん、肺がん、腎臓がん、または甲状腺がんなどのがんに罹患した被験体に施される処置は、転移を発症する確率の高さが関連することに基づいて異なり得る。転移を有する確率が高い場合、最適な処置には、化学療法のような全身処置が含まれる。
本発明者らは、乳房腫瘍の異種移植片によって生じる骨転移の転移増殖モデルにおけるPHTLHの阻害により転移内の骨溶解性病変の数が減少することを述べた。これは、発現が乳房腫瘍中のc−MAF発現の増加に応答して増加する(または発現が乳房腫瘍中のc−MAF発現の減少に応答して減少する)遺伝子がER+乳がんからの骨転移過程における原因標的遺伝子であり、したがって、それを阻害することは、乳がん転移の出現の停止に有用であり得ることを示す。
−RNA鎖のフルオロフォアなどの機能的反応物との結合体、
−異なる2’位のヒドロキシル官能基での修飾によるRNA鎖の末端、特に3’末端の修飾物、
−2’−O−メチルリボースp2’−O−フルオロリボースなどの2’位でO−アルキル化された残存物などの修飾糖を有するヌクレオチド、
−ハロゲン化塩基(例えば、5−ブロモウラシルおよび5−ヨードウラシル)、アルキル化塩基(例えば、7−メチルグアノシン)などの修飾塩基を有するヌクレオチド。
−PTHLH短縮バリアント(配列LLHDKGKSIQDLRRRFFLHHLIAEIHTA(配列番号8)を有するhPTHrP(7−34)、PTHrP(3−34)、PTHrP(8−34)、PTHrP(9−34)、PTHrP(10−34)など)ならびにアミド化バリアント、ならびにPTHLHの10位、11位、および12位に対応するアミノ酸のそれぞれAsn(Asn10バリアント)、Leu(Leu11バリアント)、およびD−Trp(D−Trp12バリアント)による置換により生じるバリアント、および特に、ペプチド[Nle8,18、Tyr34]bPTH(7−34)NH2、[Tyr34] bPTH(7−34)NH2、hPTHrP(7−34)、[Leu11、D−Trp12]hPTHrP(7−34)2、[Asn10Leu11]hPTHrP(7−34)−NH2、および[Asn10、Leu11、D−Trp12]hPTHrP(7−34)−NH2(Nuttら,1990,Endocrinology 127:491−493 ,Doppeltら,1986,Proc.Natl.Acad.Sci.USA 83:7557−7560ならびに米国特許第6362163号および同第5527772号に記載)。
−ペプチドNCT00051779(Chugai Pharmaceuticals)
−米国特許出願公開第2007203071AA号の表1〜5に記載のペプチド
−その構造がWO04103273A2号の式1に示されるペプチド
−Olstadら(Peptides 1995,16:1031−1037)およびRoubiniら(Biochemistry,1992,31:4026−4033)による記載のペプチド
−Nuttら(Endocrinology,1990,127:491−3)に記載のペプチド[Asn10Leu11]−PTHrP(7−34)−NH2および[Asn10,leu11,D−Trp12]−PTHrP−(7−34)−NH2
−任意の前述のペプチドのFc結合体(WO04060386号による記載のペプチドなど)
−これらのペプチドの機能的に等価なバリアント。
本発明者らは、RERG遺伝子発現レベルがc−MAF発現レベルと逆相関し、乳房腫瘍RERG発現の増加が転移細胞数を低下させることができることを示した。したがって、これは、発現がc−MAFによって下方制御される遺伝子発現の調整を乳がん転移の処置および/または予防のために使用することができることを証明している。この場合、本発明者は、RERG活性化剤の使用により転移細胞数を低下させることができることを示した。
−ストロメライシン3プロモーター(Bassetら,Nature 348.:699,1990)
−ムチン様糖タンパク質(DF3,MUCI)のプロモーター((Abeら Proc.Natl.Acad.Sci.U.S.A.90:282,1993)
−c−erbB−3プロモーター、c−erbB−2プロモーター、またはc−erbB−4プロモーター
−マウス乳腺腫瘍ウイルス(MMTV)のプロモーター,
−ホエイ酸性タンパク質のプロモーター
−ヒトα−ラクトアルブミンプロモーター
−ヒツジβ−ラクトグロブリンプロモーター。
(i)RERGをコードする核酸またはRERGの機能的に等価なバリアントおよび
(ii)RERGタンパク質または機能的に等価なバリアントRERG
からなる群から選択される。
発現が腫瘍、特に乳房腫瘍、結腸腫瘍、肺腫瘍、腎臓腫瘍、または甲状腺腫瘍、より特に乳房腫瘍中のc−MAFの発現レベルの増加に応答して増加するか、発現が腫瘍、特に、乳がん、結腸がん、肺がん、腎臓がん、または甲状腺がん、より特に乳がん中のc−MAFの発現レベルの減少に応答して減少する遺伝子の発現を阻害する薬剤、発現が腫瘍、特に乳房腫瘍、結腸腫瘍、肺腫瘍、腎臓腫瘍、または甲状腺腫瘍、より特に乳房腫瘍中のc−MAFの発現レベルの増加に応答して増加するか、発現が腫瘍、特に乳房腫瘍、結腸腫瘍、肺腫瘍、腎臓腫瘍、または甲状腺腫瘍、より特に乳房腫瘍中のc−MAFの発現レベルの減少に応答して減少する遺伝子の発現産物の活性を阻害する薬剤、発現が腫瘍、特に、乳房腫瘍、結腸腫瘍、肺腫瘍、腎臓腫瘍、または甲状腺腫瘍、より特に乳房腫瘍中のc−MAFの発現レベルの増加に応答して減少するか、発現が腫瘍、特に、乳房腫瘍、結腸腫瘍、肺腫瘍、腎臓腫瘍、または甲状腺腫瘍、より特に乳房腫瘍中のc−MAFの発現レベルの減少に応答して増加する遺伝子の発現を刺激する薬剤、および/または発現が腫瘍、特に乳房腫瘍、結腸腫瘍、肺腫瘍、腎臓腫瘍、または甲状腺腫瘍、より特に乳房腫瘍中のc−MAFの発現レベルの増加に応答して減少するか、発現がc−MAFの発現レベルの減少に応答して増加する遺伝子の発現産物の活性を刺激する薬剤を、典型的には、薬学的に許容され得るキャリアと組み合わせて投与する。
本発明者らは、乳がんに罹患した患者が転移を生じる性向/感受性に関する遺伝子を同定することが可能である方法を開発した。この方法論は、乳房腫瘍中の発現がc−MAFの発現に相関し、乳がん細胞株中の発現がc−MAFの発現レベルの変化に応答して変化することが認められる遺伝子の同定に基づく。
(i)原発性乳がん腫瘍サンプル中の候補遺伝子およびc−MAF遺伝子の発現レベルを決定する工程、および
(ii)c−MAF遺伝子発現の調整に応答した乳がん細胞の集団中の前記候補遺伝子の発現レベルの変化を決定する工程
を含み、
ここで、前記遺伝子の発現レベルが原発性がん腫瘍サンプル、特に、乳がん、結腸がん、肺がん、腎臓がん、または甲状腺がん、より特には乳がんの腫瘍サンプル中のc−MAFの発現と統計学的に有意に相関することが証明され、c−MAF遺伝子の発現の改変の結果としての発現レベルの変化が前記遺伝子レベルの変化と統計的に相関することが証明され、このことは、前記遺伝子が患者の転移の性向/傾向のマーカーであることを示す、方法に関する。
−ストロメライシン3のプロモーター(Bassetら,Nature 348:699,1990)
−ムチンに類似する糖タンパク質(DF3,MUCI)のプロモーター((Abeら,Proc.Natl.Acad.Sci.U.S.A.90:282,1993)
−プロモーターc−erbB−3、c−erbB−2、またはc−erbB−4
−マウス乳腺腫瘍ウイルス(MMTV)のプロモーター
−ホエイ酸性タンパク質のプロモーター
−ヒトα−ラクトアルブミンのプロモーター
−ウシβ−ラクトグロブリンのプロモーター 。
(i)原発性がん腫瘍サンプル中の前記遺伝子およびc−MAF遺伝子の発現レベルの比較、および
(ii)c−MAF遺伝子発現の調整に応答した発現レベルの、前記遺伝子レベルの変化との比較
を含む。
実験研究モデル
乳がんER+およびER−PR−Her2−の転移研究のための新規の実験モデルを開発した。この目的を達成するために、MCF7として公知の乳がんER+のヒト細胞株(GFP/ルシフェラーゼを発現させるベクターを使用して安定な形態でトランスフェクトされたもの)を使用した。種々の器官で転移能力を有する細胞を選択することができるように、この細胞株を、室内または(尾)尾静脈への注射によって免疫不全マウス(Balb−c/ヌード)に接種した。ラットにエストロゲンの皮下移植を行って、実験期間中これらのホルモンの存在を保証した。
異なる組織中の転移性集団を、転移性病変由来の細胞の同定および単離によって選択した。これのために、異なる時間で目的の器官内の腫瘍細胞の確立および成長を検出し、腫瘍性細胞の存在数を定量することが可能であるテクノロジーを導入した生物発光画像化技術を使用した。このテクノロジーの適用のために、ルシフェラーゼおよびGFPの遺伝子を発現するように細胞に形質導入したが、これらについて非侵襲性の方法を使用してin vivoにてリアルタイムでモニタリング/観察が可能である。その感度および速度のレベルに起因する好ましい方法としてXenogen IVISタイプの装置およびLivingimageソフトウェアを使用して、全身麻酔下の動物についての発光画像(ルシフェラーゼ活性)をキャプチャーする。転移性細胞を単離するために、腫瘍病変を切開し、次いで、レーザー誘起蛍光(GFP)(緑色蛍光タンパク質)での掃引を使用した細胞数測定技術を使用して宿主生物の転移性細胞を他の細胞から単離する。一旦これらの細胞が単離されると、特異的組織を介するその向性を富化/供給するためにこのプロセスを繰り返す。これらの手順を使用して、組織特異性を有する特異的転移性集団(骨および脳への転移が含まれる)を単離した。
349個の原発性乳房腫瘍のゲノムワイドな転写プロフィールの比較により、発現がc−MAFの発現と良好に正に(直接)相関する遺伝子を同定し、または良好に負に(逆)相関する遺伝子を同定した。この様式で得た遺伝子を、所定の細胞モデルにおけるc−MAF発現と比較したその発現の分析によって確認した。MCF7 ER+乳がん細胞株を、これらの細胞株がc−MAF遺伝子の長いアイソフォームまたは短いアイソフォームを十分に発現するように改変し、Affymetrix U133A2Plusを使用してRNAmの発現プロフィールを決定した。日常的なテクノロジーを使用して、c−MAFが枯渇したMCF−7骨転移細胞の派生物を得た。前述の細胞集団の遺伝子発現プロフィールを決定し、c−MAFの発現の機能として有意に改変された遺伝子を選択した。これらの結果により、骨へのc−MAFの転移プログラムを得ることが可能となり、それには99個の遺伝子が含まれ(これらのうちの76個の遺伝子が過剰発現され(表1)、33個の遺伝子が抑制された(表2))、その発現は原発性乳がん腫瘍内のc−MAFの発現レベルと有意に相関し、使用される少なくとも1つの細胞条件下でc−MAFの機能によって変化する。骨へのc−MAFの転移プログラムには、サイトカイン、細胞接着分子、膜に係留したプロテアーゼ、シグナル伝達メディエーター、および転写因子が含まれる。
転移が豊富な遺伝子群を得てその臨床相関を検証するために、R統計パッケージおよびBioconductorを使用した。データ処理のための特定の機能および構造をインポートし、ウェブサイトwww.bioconductor.orgにて公的オープンアクセス可能である。
関連遺伝子の選択
c−MAFの発現レベルの変化に応答して単一のER+乳がん細胞株由来の細胞において差次的様式で発現する遺伝子を選択することを目的とする分析を行った(表1、図1B)。c−MAFによって媒介される骨転移プログラムを決定づける遺伝子および機能を、以下の基準にしたがって選択した:
i)原発性腫瘍中での発現がc−MAFの発現に有意に相関する遺伝子、
ii)c−MAFがMCF7細胞中で過剰発現される場合(長いアイソフォームまたは短いアイソフォーム)またはc−MAFを発現するMCF7に由来する高転移性骨細胞中のc−MAF発現が低下する場合に、発現がc−MAF発現で改変される遺伝子、および
iii)原発性腫瘍およびii)中の言及された細胞条件の1つにおけるMAFの発現に相関する遺伝子が、c−MAFによって媒介される骨転移プログラムのメンバーと見なされること。
骨転移の発症で富化される遺伝子の治療的価値および予後的価値
本明細書中で開発した転移性細胞集団の選択のための実験系によって骨転移で富化した遺伝子を、乳がんに罹患した患者由来の560個の原発性乳がん腫瘍および58個の転移物の発現プロフィールおよび臨床記録を含む2つの異なるデータベースの比較によって評価した。これらの腫瘍は、乳がんの全てのサブタイプおよび転移の局在を代表する。データベースおよび関連する臨床記録の両方を公的に入手可能である(GSE 2603、2034、12276、および14020)。
c−MAFによって媒介された骨転移についてのプログラムのメンバーのin vivoでの機能確認:PTHLH遺伝子
先の分析中に陽性を示し、且つc−MAFの発現に直接相関する転移性PTHLH遺伝子(表1および図3)を、マウスの乳がん転移の異種移植片実験モデルにおける骨転移増殖試験で機能的に確認した。候補遺伝子が転移のプロセスを指示することを確認するための標準的な近似/アプローチは、c−MAFを発現する低転移性細胞におけるPTHLH機能の損失のサンプルであった。c−MAF遺伝子の発現は、in vivoで骨への転移が中程度の細胞MCF7で誘導され、この細胞は遺伝子c−MAFの低レベルの発現を示す。c−MAFの過剰発現は、PTHLH遺伝子の内因性レベルの増加を担っていた(図3)。この文脈では、次いで、サイトカインPTHLHの活性を、アンタゴニストペプチドを使用して遮断した(図3)。
c−MAF遺伝子によって媒介される骨転移プログラムのメンバーのin vivo機能確認;RERG遺伝子
転移抑制遺伝子RERGは、増殖に関与する。実施した先の分析は、RERG遺伝子の発現がc−MAFの発現と逆相関することを実証した(表2および図2)。RERG遺伝子を、ラットの乳がん転移異種移植実験モデルにおいて骨における転移増殖試験で機能的に確認した。
c−MAFによって媒介される骨転移プログラムのメンバーのin vivo機能確認:PODXL遺伝子
先の分析で陽性であり、且つc−MAFの発現に直接相関するPODXL転移性遺伝子(表1および図4)を、マウス由来の精製骨髄細胞に基づいた実験モデルにおける骨髄由来の細胞への接着試験で機能的に確認した。脈管構造から採取した内皮細胞または肺の細胞外基質由来のタンパク質を使用して接着過程を繰り返した場合に、PODXLの存在下でのより高い接着およびより高レベルのc−MAFのいずれも認められないが、むしろ正反対であることを考慮すると、この接着過程は骨細胞特異的である(図4)。候補遺伝子が転移過程を指示することを確認するための標準的な近似は、高転移性細胞(骨細胞または内皮細胞のいずれか)における機能喪失試験であった。PODXL遺伝子の発現は、in vivoで骨への転移性が高い細胞MCF7で低下し、高レベルのc−MAF遺伝子発現がPODXL遺伝子の内因性レベルの増加を担うことを示していた。
Claims (33)
- 被験体における乳がんの転移をin vitroで予測する方法であって、該被験体から採取した腫瘍性組織のサンプルにおける、1つ以上の遺伝子であって、その発現が該腫瘍中のc−MAFの発現レベルの増加に応答して調整される1つ以上の遺伝子の発現レベルを決定する工程を含み、基準値と比較した該1つ以上の遺伝子の発現レベルの変化が転移発生リスクの高さを示す、方法。
- 前記1つ以上の遺伝子であって、その発現がc−MAFの発現レベルの増加に応答して調整される1つ以上の遺伝子が、表1に取り上げた遺伝子および表2中に示す遺伝子から形成される群から選択され、該1つ以上の遺伝子の発現レベルの調整が表1に取り上げた1つ以上の遺伝子の発現の増加および/または表2中に示す1つ以上の遺伝子の発現の減少である、請求項1に記載の方法。
- 前記1つ以上の遺伝子であって、その発現がc−MAFの発現レベルの増加に応答して調整される遺伝子が、PTHLH、PODXL、およびRERGの群から選択される、請求項2に記載の方法。
- 乳がんに罹患した被験体のための個別化治療をin vitroでデザインする方法であって、該被験体から採取した腫瘍性組織サンプルの、1つ以上の遺伝子であって、その発現がc−MAFの発現レベルの増加に応答して調整される1つ以上の遺伝子の発現レベルの決定を含み、基準値と比較した該1つ以上の遺伝子の発現レベルの変化が、該被験体が転移予防のための処置を受けるのに適切であること示す、方法。
- 前記1つ以上の遺伝子であって、その発現がc−MAFの発現レベルの増加に応答して調整される1つ以上の遺伝子が、1つ以上の表1中に含まれる遺伝子および/または1つ以上の表2中に示された遺伝子によって形成される群から選択され、1つ以上の表1由来の遺伝子の発現レベルの調整が発現の増加を示し、そして/または1つ以上の表2由来の遺伝子の発現レベルの調整が発現の減少を示す、請求項4に記載の方法。
- 前記遺伝子であって、その発現がc−MAFの発現レベルの増加に応答して調整される遺伝子が、PTHLH、PODXL、およびRERGの群から選択される、請求項5に記載の方法。
- 前記乳がんが、ER+がんおよびトリプルネガティブがんからなる群から選択される、請求項1〜6に記載の方法。
- 前記転移が骨転移である、請求項1〜7のいずれかに記載の方法。
- 前記骨転移が骨溶解性転移である、請求項9に記載の方法。
- 前記1つ以上の遺伝子であって、その発現がc−MAFの発現レベルの増加に応答して調整される1つ以上の遺伝子の発現レベルの決定を、該遺伝子のRNAmの発現レベルの決定中に実施する/行う、請求項1〜9のいずれかに記載の方法。
- c−MAFの発現レベルの増加に応答して調整される前記1つ以上の遺伝子の発現レベルの決定を、該遺伝子によってコードされるポリペプチドの発現レベルの決定中に実施する、請求項1〜9のいずれかに記載の方法。
- 乳がんの転移の処置および/または予防のための医薬の調製のための、遺伝子の発現または該遺伝子の発現産物の活性を阻害するための薬剤の使用であって、乳がん腫瘍細胞中での該遺伝子の発現が、該細胞中のc−MAFの発現レベルの増加に応答して増加するか、前記細胞中のc−MAFの発現レベルの減少に応答して減少することによって該遺伝子が特徴づけられる、使用。
- 遺伝子発現を阻害する前記薬剤が、該遺伝子に特異的なsiRNA、該遺伝子に特異的なアンチセンスオリゴヌクレオチド、該遺伝子に特異的なリボザイムから選択されるか、該遺伝子の発現産物の活性を阻害する薬剤が、該発現産物に特異的なインヒビター抗体、該発現産物のドミナントネガティブバリアント、および該発現産物由来の阻害性ペプチドによって形成される群から選択される、請求項12に記載の使用。
- 前記遺伝子であって、その発現が乳房腫瘍内のc−MAFの発現レベルの増加に応答して増加するか、その発現が乳房腫瘍内のc−MAFの発現レベルの低下に応答して減少する遺伝子が、表1中に記載の遺伝子から選択される、請求項12または13に記載の使用。
- 前記遺伝子であって、その発現が乳房腫瘍内のc−MAFの発現レベルの増加に応答して増加する遺伝子が、PHTLH遺伝子またはPODXL遺伝子である、請求項14に記載の使用。
- 乳がんの転移の処置および/または予防のための医薬の調製のための、遺伝子の発現または該遺伝子の発現産物の活性を刺激するための薬剤の使用であって、乳がん腫瘍細胞中での該遺伝子の発現が、該細胞中のc−MAFの発現レベルの増加に応答して減少するか、該遺伝子の発現が、該細胞中のc−MAFの発現レベルの減少に応答して増加することによって該遺伝子が特徴づけられる、使用。
- 前記遺伝子の発現を刺激する前記薬剤が、該遺伝子のコード配列を含むポリヌクレオチドであるか、前記遺伝子産物の活性を刺激する前記薬剤が該遺伝子によってコードされるポリペプチドである、請求項16に記載の使用。
- 前記遺伝子であって、その発現が乳房腫瘍中のc−MAFの発現レベルの増加に応答して減少するか、その発現が乳房腫瘍中のc−MAFの発現レベルの減少に応答して増加する遺伝子が、表2中に記載の遺伝子から選択される、請求項17に記載の使用。
- 前記遺伝子であって、その発現が乳房腫瘍中のc−MAFの発現レベルの増加に応答して減少する遺伝子がRERG遺伝子である、請求項18に記載の使用。
- 前記乳がんが、ER+がんおよびトリプルネガティブがんによって形成される群から選択される、請求項12〜19のいずれかに記載の使用。
- 転移が骨転移である、請求項12〜20に記載の使用。
- 前記骨転移が骨溶解性転移である、請求項21に記載の使用。
- 乳がんに罹患している被験体における転移性向についての遺伝子マーカーをin vitroで同定する方法であって、
(i)乳がんの原発性腫瘍サンプル中の候補遺伝子およびc−MAFの発現レベルを決定する工程、および
(ii)該c−MAF遺伝子の発現の調整に応答した乳がん細胞集団中の該遺伝子の発現レベルの変化を決定する工程を含み、
ここで、該遺伝子の発現レベルが該乳がんの原発性腫瘍サンプル中のc−MAFの発現に統計的に有意に相関し、c−MAF遺伝子発現の調整に応答した発現レベルの変化が該遺伝子のレベルの変化に統計的に有意に相関する場合、これは、該遺伝子が被験体における転移の性向についてのマーカーであることを示す、方法。 - 工程(i)で決定された所与の遺伝子の発現が前記原発性腫瘍サンプル中のc−MAFレベルと直接相関し、c−MAF遺伝子発現の調整に応答した発現レベルの変化が該調整に直接相関する場合、これは、該遺伝子のレベルの高さが転移性向を示す、請求項23に記載の方法。
- 工程(i)で決定された所与の遺伝子の発現が前記原発性腫瘍サンプル中のc−MAFレベルと逆相関し、c−MAF遺伝子発現の調整に応答した発現レベルの変化が該調整に逆相関する場合、これは、該遺伝子レベルの低下が転移性向を示す、請求項23に記載の方法。
- c−MAF発現の前記調整が前記発現の増加である、請求項23〜25のいずれかに記載の方法。
- 発現の前記増加が前記c−MAFの短いアイソフォームおよび/または長いアイソフォームの前記細胞集団の発現により達成される、請求項26に記載の方法。
- c−MAF発現レベルの前記調整が前記発現の減少である、請求項23〜25のいずれかに記載の方法。
- c−MAFの短いアイソフォームおよび/または該c−MAFの長いアイソフォームの発現が減少する、請求項28に記載の方法。
- 前記乳がん細胞および/または前記原発性腫瘍がER+またはトリプルネガティブである、請求項23〜29のいずれかに記載の方法。
- 前記転移が骨転移である、請求項23〜30のいずれかに記載の方法。
- 前記乳がん細胞が樹立細胞株に由来する、請求項23〜31のいずれかに記載の方法。
- 前記樹立細胞株がMCF7株である、請求項32に記載の方法。
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KR20150122786A (ko) | 2013-03-15 | 2015-11-02 | 펀다시오 인스티튜트 드 르세르카 바이오메디카 (아이알비 바르셀로나) | 암 전이의 진단, 예후 및 치료를 위한 방법 |
WO2014184679A2 (en) | 2013-03-15 | 2014-11-20 | Inbiomotion S.L. | Method for the prognosis and treatment of renal cell carcinoma metastasis |
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HUE044823T2 (hu) | 2014-06-17 | 2019-11-28 | Igenomix S L | Õssejtterápia méhnyálkahártya-patológiákban |
KR102465120B1 (ko) | 2014-07-17 | 2022-11-10 | 노보 노르디스크 에이/에스 | 점도를 감소시키기 위한 trem-1 항체의 부위 지정 돌연변이유발 |
EP3229909B1 (en) | 2014-12-11 | 2020-10-14 | Inbiomotion S.L. | Binding members for human c-maf |
MX2018014279A (es) | 2016-05-25 | 2019-07-08 | Inbiomotion Sl | Tratamiento terapeutico de cancer de mama con base en estado de c-maf. |
CA3082728A1 (en) | 2017-11-22 | 2019-05-31 | Inbiomotion S.L. | Therapeutic treatment of breast cancer based on c-maf status |
-
2014
- 2014-03-14 KR KR1020157027318A patent/KR20150122786A/ko not_active Application Discontinuation
- 2014-03-14 US US14/776,453 patent/US20160040247A1/en not_active Abandoned
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- 2014-03-14 EP EP17181286.0A patent/EP3272880B1/en active Active
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- 2014-03-14 JP JP2015562396A patent/JP2016518815A/ja active Pending
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- 2014-03-14 MX MX2015011373A patent/MX368575B/es active IP Right Grant
- 2014-03-14 EP EP14752365.8A patent/EP2975138A2/en not_active Withdrawn
- 2014-03-14 CN CN201480015519.5A patent/CN105431548A/zh active Pending
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2016
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Also Published As
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AU2014229563A1 (en) | 2015-10-01 |
KR20150122786A (ko) | 2015-11-02 |
MX2015011373A (es) | 2016-06-10 |
CN105431548A (zh) | 2016-03-23 |
EP3272880A2 (en) | 2018-01-24 |
EP2975138A2 (en) | 2016-01-20 |
US20160040247A1 (en) | 2016-02-11 |
EP3272880A3 (en) | 2018-04-11 |
WO2014140896A2 (es) | 2014-09-18 |
US20190309299A1 (en) | 2019-10-10 |
AU2014229563B2 (en) | 2020-04-09 |
WO2014140896A3 (es) | 2015-05-21 |
US20140314792A1 (en) | 2014-10-23 |
US20170002357A1 (en) | 2017-01-05 |
BR112015023510A2 (pt) | 2017-10-10 |
CA2903306A1 (en) | 2014-09-18 |
WO2014140896A9 (es) | 2019-01-03 |
US11591599B2 (en) | 2023-02-28 |
US20230323356A1 (en) | 2023-10-12 |
EP3272880B1 (en) | 2020-11-25 |
MX368575B (es) | 2019-10-08 |
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