JP2016506412A - 癌の増殖及び転移の阻害 - Google Patents
癌の増殖及び転移の阻害 Download PDFInfo
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Abstract
Description
本出願は、2012年12月24日出願のオーストラリア仮特許出願番号第2012905692号明細書及び2013年4月5日出願のオーストラリア特許出願番号第2013202668号明細書の優先権を主張し、ここに言及することによって、それらの内容を本明細書中に援用するものとする。
対象におけるFlightless Iの発現及び/又は活性レベルを測定する工程;
対象におけるFlightless Iの発現及び/又は活性レベルを、Flightless Iの発現及び/又は活性の参照レベルと比較する工程;及び
比較に基づき、対象において癌を診断する工程。
対象におけるFlightless Iの発現及び/又は活性レベルを測定する工程;
対象におけるFlightless Iの発現及び/又は活性レベルを、Flightless Iの発現及び/又は活性の参照レベルと比較する工程;及び
比較に基づき、対象が癌を発生しやすいかどうかを判定する工程。
対象におけるFlightless Iの発現及び/又は活性レベルを測定する工程;
対象におけるFlightless Iの発現及び/又は活性レベルを、Flightless Iの発現及び/又は活性の参照レベルと比較する工程;及び
比較に基づき、対象における癌の進行を査定する工程。
対象におけるFlightless Iの発現及び/又は活性レベルを測定する工程;
対象におけるFlightless Iの発現及び/又は活性レベルを、Flightless Iの発現及び/又は活性の参照レベルと比較する工程;及び
比較に基づき、対象において癌を診断する工程。
対象におけるFlightless Iの発現及び/又は活性レベルを測定する工程;
対象におけるFlightless Iの発現及び/又は活性レベルを、Flightless Iの発現及び/又は活性の参照レベルと比較する工程;及び
比較に基づき、対象が癌を発生しやすいかどうかを判定する工程。
対象におけるFlightless Iの発現及び/又は活性レベルを測定する工程;
対象におけるFlightless Iの発現及び/又は活性レベルを、Flightless Iの発現及び/又は活性の参照レベルと比較する工程;及び
比較に基づき、対象における癌の進行を査定する工程。
(0204) 腫瘍細胞の上皮間葉転換、続く分化、浸潤、付着、及び遊走は、腫瘍の発生及び進行を理解するのに、ならびに新規療法の開発において重要である。細胞応答を仲介するのに重要な細胞骨格タンパク質の1種が、Flightless Iである。Flightless Iは、その二連ドメイン構造を通じて、独自に、多数の構造タンパク質及びシグナル伝達タンパク質と相互作用すること、及び細胞のシグナル伝達事象を細胞骨格再造形へと変換することができ、従って、信号伝達経路とアクチン細胞骨格とを結び付けることができる。
(0209) Flightless I遺伝子導入マウスを含むマウスで化学的に誘導される扁平上皮癌(SCC)の十分に記載がなされたモデル(腫瘍の誘導を100%もたらすモデル−60%はSCC、40%は肉腫)を用いて、in vivoでの原発性SCCの発生におけるFlightless Iレベルの低下、正常、上昇の効果を研究した。Flightless Iに関してヘテロ接合性であるマウス(すなわちFlightless Iのコピーを1つ発現するマウス−Flii+/-)野生型マウス(すなわちFlightless Iのコピーを両方発現するマウス−WT)及びFlightless Iを過剰発現する遺伝子導入マウス(すなわちFlightless Iのコピーを余分に発現するマウス−FliiTg/Tg)(n=12)で、右側腹部に3−メチルコラントレン(MCA)を500μg含有するコーン油0.1mlを皮内注射して、SCCを誘導した。原発性腫瘍の発生についてマウスを週に2回観察した。観察として、腫瘍の写真撮影、電子ノギスによる腫瘍体積の測定、及び腫瘍の発生進行の臨床スコアの採点を行った。12週間という期間の終わりに、マウスをCO2及び頸椎脱臼で安楽死させて、組織学的分析及びサイトケラチン染色用の腫瘍試料を採取し、腫瘍がSCCであることを確認した。
(0213) 扁平上皮癌(SCC)は、皮膚の水疱形成症状である表皮水疱症(EB)を患っている患者に特有の問題である。米国でEB患者で20年間行われた研究は、全身性の重篤な劣性栄養障害性EB(RDEB)である患者の55歳におけるSCC発生の累積危険度及びそれに続く死亡が、それぞれ、90%及び78%を超えることを示した(South AP and O’Toole EA, 2010, Dermatol. Clin., 28: 171−178)。また、RDEBの小児は、SCCを発生する危険性が高まる(母集団における生涯危険度が1.35〜2.7%であるのに対して、12歳で2.5%)(Fine JD et al., 2009, J. Am. Acad. Dermatol., 60: 203−211)。
(0219) SCC細胞株及びRDEB−SCCケラチン生成細胞におけるFlightless I発現を、上記に詳細に記載したとおりに、ウェスタン分析法及び免疫組織化学的検査法を用いて測定した。SCC細胞株(SCC−IC1、SCC−IC2、及びMET−1)を、上記の実施例1で記載したとおりに培養し、一方ヒトRDEB−SCCケラチン生成細胞(CC、SBK、及びGP)は、最初に、プロテアーゼ阻害剤カクテル(Roche、UK)及び10mMのEDTAを含有する1×トリトン溶解緩衝液(20mMのトリス(pH7.4)、137mMのNaCl、2mMのEDTA(pH7.4)、1%トリトンX−100、及び10%グリセロール)で溶解させてから、ウエスタンブロット法を行った。Flightless Iに結合するタンパク質であるFLAP−1の発現も、SCC細胞株のSCC−IC1及びMET−1で測定した。この実験で用いた一次抗体は、Aviva Systems Biologyから購入した抗FLAP−1ウサギポリクローナル抗体(ARP59016_P050)であり、二次抗体は、Dako An agilent Technologies Companyから購入したポリクローナルヤギ抗ウサギIgG−HRP(PO488)であった。
(0222) EB−SCCの三次元器官型モデルを用いて、SCC腫瘍細胞の浸潤性質に対してFlightless I発現の減少が持つ効果を明らかにした。簡単に述べると、既に記載されたとおりに、コラーゲン:マトリゲルのゲル上で器官型培養を行った(Martins et al., 2009, J. Cell Sci., 122: 1788−1799)。コラーゲン:マトリゲルのゲルは、3.5体積分のI型コラーゲン(First Link、UK)、3.5体積分のマトリゲル(BD Biosciences、UK)、1体積分の10×DMEM、1体積分のFCS、及び1体積分の10%FCS/HFF含有DMEM(5×106/ml密度で再懸濁させる)を混合して調製した。24ウェルプレートの各ウェルにゲル混合物1mlを入れ、37℃で1時間重合させた。重合後、1ウェルあたり1mlのDMEMを添加し、ゲルを18時間インキュベートして、平衡化した。SBK、GP、MET−1、及び/又はCC細胞を、1つのゲルあたり5×105密度で、ゲル表面に置いたプラスチックリング内に蒔いた。細胞は、rFLAP−1(100ng/ml)、Flightless I中和抗体(FnAB−100μg/ml)、投与量が一致したIgG対照抗体、又はPBS対照を含有する培地に蒔いた。rFLAP−1タンパク質は、Abnova Technologiesから購入した(LRRFlP1(657−784)タンパク質−H00009208−Q01)。Flightless I中和抗体は、自家製であり、Flightless Iタンパク質のロイシンリッチリピート(LRR)ドメインに対して産生されたマウスモノクローナル抗Flightless(FnAb)IgG1抗体を親和性精製したものであった。24時間後、プラスチックリングを取り除き、ゲルをステンレス鋼格子に乗せて気液界面まで持ち上げた。rFLAP−1、FnAb、IgG対照、又はPBS対照を含有する培地を2日ごとに交換し、10日目にゲルを収穫して、4%パラホルムアルデヒド(PFA)で固定し、パラフィンに包埋した。浸潤SCC細胞(SBK及びGP−実施例4用)のパラフィン切片を、上記の免疫組織化学的プロトコルを用いて、Flightless I発現に関して染色した。rFLAP−1、FnAB、IgG対照、又はPBS対照で処理した浸潤孤発性SCC細胞(MET−1)及びEB−SCC細胞(CC)のパラフィン切片は、AnalySISソフトウェアパッケージ(Soft−Imaging System GmbH、Munster、Germany)で測定して浸潤している深さまでヘマトキシリン及びエオシンで染色するか、又は上記のとおりの、Flightless及びTGF−β1発現(実施例6)ならびに共在化分析に用いた。
(0224) SCC細胞浸潤及び腫瘍増殖に対するFlightless Iの効果の背後にある機構として考えられるものの1つは、TGF−βシグナル伝達経路に対するFlightless Iの効果である。TGF−βシグナル伝達は、癌の浸潤及び転移の手段であり、EB患者におけるSCC発生に寄与している(Ng YZ et al., 2012, Cancer Res., 72: 3522−3534)。上記の実施例5で記載した方法に従い、免疫組織化学的検査法を用いて、rFLAP−1又はPBS対照で処理した3D器官型SCC(CC)又はRDEB−SCC(MET−1)ゲルにおいて、TGF−β1発現に対してFlightless Iの発現減少(rFLAP−1による)が持つ効果を調査した。結果は、rFLAP−1処理を行うと、Flightless I発現を減少させることができ、これに続いてTGF−βシグナル伝達が減少することを示した(図13A及び図13B)。浸潤性過剰増殖性癌性細胞は、Flightless I発現が顕著に多い。まとめると、これらの結果は、Flightless I発現を調節することが、SCC及びEB−SCC病理の両方において、TGF−βシグナル伝達を介したSCCの発生、増殖、及び浸潤を減少させるのに有効である可能性があることを示す。
(0225) 24匹の年齢及び性別が一致した野生型Balb/cマウス(4〜6週齢、体重約18グラム)に、3−メチルコラントレン(500μgのMCAを含有する100μlのコーン油)を1回皮内注射して、原発性皮膚SCCを誘導した。投与は、各マウスの背中の指定された場所に行った。MCA注射後、マウスは炎症性病変を発生しはじめ、病変は更に進行して、試験の約7週間で、潰瘍性病変になり、SCC誘導から9週間後、壊死性潰瘍性結節性SCCになった。自家製のFlightless Iに対する中和抗体(FnAb)100μl(50μg/ml)又は用量一致のIgG対照抗体を2週間ごとに(00、2、4、6、及び8週目を含む)、4回の皮内注射(025μl)にて、最初のMCA注射部位又はその後の時点の腫瘍基部周囲に投与することにより、Flightless I(Flii)発現/活性を減少させた(n=12/治療1種類)。実験の10週目にマウスを安楽死させた。この時点で、壊死性潰瘍性結節性SCCは十分に発達しており、非損傷性及び損傷性腫瘍皮膚の試料を採取して、既に記載したとおり、組織学検査及び免疫蛍光法用に10%ホルマリンで固定及び処理するか、mRNA及びタンパク質抽出用に顕微解剖して急速凍結するかのいずれかを行った。SCC発生は、確立されたプロトコルに従って、in−vivo及びex−vivoで電子ノギスを用いて顕微鏡観察により分析した。プロトコルには、腫瘍上皮の長さ、腫瘍断面積の幅、及び腫瘍体積の顕微鏡による分析が含まれる。
(0229) 他の型の癌におけるFlightless I発現の効果を検査するため、遺伝子導入Flightlessマウスで原発性及び転移性腫瘍の発生を検査した。CT26マウス結腸癌細胞を用いて、Flii+/-(Flightless Iを過少発現するマウス)、WT、及びFliiTg/-(Flightless Iを過剰発現するマウス)のメスのマウス(6〜8週齢)に、原発性及び転移性腫瘍を誘導した。原発性腫瘍を誘導するため、細胞を側腹部の真皮に注射した。具体的には、100μlの注射体積で細胞5×105個を用いた。注射後毎日、原発性腫瘍を電子ノギスで測定した。次いで、注射から19日後、動物をと殺して、原発性腫瘍の重さを測定し、組織学的検査用に固定した。転移性モデルについては、CT26細胞を3×105個、マウスの尾静脈に注射し、と殺(14日目)して肺を取り出した。この時点で、(肺表面において)顕微鏡観察で視認できる腫瘍転移を計数し(werecounted)、上記のとおり、肺の重さを測定し、組織学的検査用に固定した。顕微鏡観察による原発性腫瘍の大きさ及び転移性腫瘍の数を分析した。原発性腫瘍試料及び転移性腫瘍試料の両方を、上記に詳細を記載したとおりの免疫組織化学的検査法を用いて、腫瘍間質周囲の線維芽細胞に関連した癌を示すα−SMAの発現について分析した。Flii+/-マウス及びFliiTg/-マウスから採取した原発性肺線維芽細胞は、フローサイトメトリーによってもα−SMAの発現について分析し、線維芽細胞でのα−SMA発現に対するFlightless I発現の効果を調査した。
Claims (65)
- 対象において癌を治療又は予防する方法であって、該対象においてFlightless Iの発現及び/又は活性を低下させる工程を含む、方法。
- 前記対象においてFlightless Iの前記発現及び/又は活性を低下させる工程が、前記対象に、Flightless Iの前記発現及び/又は活性を低下させる作用剤を有効量で投与することを含む、請求項1に記載の方法。
- 前記作用剤が、薬物、小分子、核酸、オリゴヌクレオチド、オリゴペプチド、ポリペプチド、タンパク質、酵素、多糖、糖タンパク質、ホルモン、受容体、受容体に対するリガンド、補因子、アンチセンスオリゴヌクレオチド、リボザイム、低分子干渉RNA、マイクロRNA、低分子ヘアピン型RNA、脂質、アプタマー、ウイルス、及び抗体又はその抗原結合部分からなる群のなかの1種又は複数より選択される、請求項2に記載の方法。
- 前記作用剤が、Flightless Iに対する中和抗体、又はその抗原結合部分である、請求項2又は請求項3に記載の方法。
- 前記作用剤が、Flightless I結合タンパク質である、請求項2又は請求項3に記載の方法。
- 前記Flightless I結合タンパク質が、FLAP−1である、請求項5に記載の方法。
- 前記癌が、皮膚癌、結腸直腸癌、及び肺癌からなる群より選択される、請求項1から6のいずれか1項に記載の方法。
- 前記皮膚癌が、扁平上皮癌である、請求項7に記載の方法。
- 癌性細胞の増殖を阻害する方法であって、該細胞においてFlightless Iの発現及び/又は活性を低下させる工程を含む、方法。
- 前記細胞においてFlightless Iの前記発現及び/又は活性を低下させる工程は、前記細胞に、Flightless Iの前記発現及び/又は活性を低下させる作用剤を有効量で投与することを含む、請求項9に記載の方法。
- 前記作用剤が、薬物、小分子、核酸、オリゴヌクレオチド、オリゴペプチド、ポリペプチド、タンパク質、酵素、多糖、糖タンパク質、ホルモン、受容体、受容体に対するリガンド、補因子、アンチセンスオリゴヌクレオチド、リボザイム、低分子干渉RNA、マイクロRNA、低分子ヘアピン型RNA、脂質、アプタマー、ウイルス、及び抗体又はその抗原結合部分からなる群のなかの1種又は複数より選択される、請求項10に記載の方法。
- 前記作用剤が、Flightless Iに対する中和抗体、又はその抗原結合部分である、請求項10又は請求項11に記載の方法。
- 前記作用剤が、Flightless I結合タンパク質である、請求項10又は請求項11に記載の方法。
- 前記Flightless I結合タンパク質が、FLAP−1である、請求項13に記載の方法。
- 前記細胞が、皮膚細胞、結腸直腸細胞、及び肺細胞からなる群より選択される、請求項9から14のいずれか1項に記載の方法。
- 前記皮膚細胞が、扁平細胞である、請求項15に記載の方法。
- 対象において腫瘍の形成及び/又は増殖を阻害する、又は対象において腫瘍の浸潤及び転移を阻害する方法であって、該対象においてFlightless Iの発現及び/又は活性を低下させる工程を含む、方法。
- 前記対象においてFlightless Iの前記発現及び/又は活性を低下させる工程は、前記対象に、Flightless Iの前記発現及び/又は活性を低下させる作用剤を有効量で投与することを含む、請求項17に記載の方法。
- 前記作用剤が、薬物、小分子、核酸、オリゴヌクレオチド、オリゴペプチド、ポリペプチド、タンパク質、酵素、多糖、糖タンパク質、ホルモン、受容体、受容体に対するリガンド、補因子、アンチセンスオリゴヌクレオチド、リボザイム、低分子干渉RNA、マイクロRNA、低分子ヘアピン型RNA、脂質、アプタマー、ウイルス、及び抗体又はその抗原結合部分からなる群のなかの1種又は複数より選択される、請求項18に記載の方法。
- 前記作用剤が、Flightless Iに対する中和抗体、又はその抗原結合部分である、請求項18又は請求項19に記載の方法。
- 前記作用剤が、Flightless I結合タンパク質である、請求項18又は請求項19に記載の方法。
- 前記Flightless I結合タンパク質が、FLAP−1である、請求項21に記載の方法。
- 前記腫瘍が、皮膚腫瘍、結腸直腸腫瘍、及び肺腫瘍からなる群より選択される、請求項17から22のいずれか1項に記載の方法。
- 前記皮膚腫瘍が、扁平細胞腫瘍である、請求項23に記載の方法。
- 対象における癌を診断する方法であって、以下の工程:
該対象におけるFlightless Iの発現及び/又は活性レベルを測定する工程;
該対象におけるFlightless Iの該発現及び/又は活性レベルを、Flightless Iの発現及び/又は活性の参照レベルと比較する工程;及び
該比較に基づき、該対象における癌を診断する工程。 - 前記対象におけるFlightless Iの発現及び/又は活性レベルがFlightless Iの発現及び/又は活性の前記参照レベルより高い場合は、前記対象に癌が存在することを示している、請求項25に記載の方法。
- Flightless Iの前記発現及び/又は活性レベルが、前記対象から得られる試料で測定される、請求項25又は請求項26に記載の方法。
- Flightless Iの前記発現レベルを測定する工程が、Flightless IのRNA又はタンパク質のレベルを測定することを含む、請求項25から27のいずれか1項に記載の方法。
- 前記Flightless IのRNAが、Flightless IのmRNAである、請求項28に記載の方法。
- 前記癌が、皮膚癌、結腸直腸癌、及び肺癌からなる群より選択される、請求項25から29のいずれか1項に記載の方法。
- 前記皮膚癌が、扁平上皮癌である、請求項30に記載の方法。
- 対象が癌を発生しやすいかどうかを判定する方法であって、以下の工程、
該対象におけるFlightless Iの発現及び/又は活性レベルを測定する工程、
該対象におけるFlightless Iの該発現及び/又は活性レベルを、Flightless Iの発現及び/又は活性の参照レベルと比較する工程、及び
該比較に基づき、該対象が癌を発生しやすいかどうか判定する工程、
を含むことを特徴とする方法。 - 前記対象におけるFlightless Iの発現及び/又は活性レベルがFlightless Iの発現及び/又は活性の前記参照レベルより高い場合は、前記対象が癌を発生しやすいことを示している、請求項32に記載の方法。
- Flightless Iの前記発現及び/又は活性レベルが、前記対象から得られる試料で測定される、請求項32又は請求項33に記載の方法。
- Flightless Iの前記発現レベルを測定する工程が、Flightless IのRNA又はタンパク質のレベルを測定することを含む、請求項32から34のいずれか1項に記載の方法。
- 前記Flightless IのRNAはFlightless IのmRNAである、請求項35に記載の方法。
- 前記癌が、皮膚癌、結腸直腸癌、及び肺癌からなる群より選択される、請求項32から36のいずれか1項に記載の方法。
- 前記皮膚癌が、扁平上皮癌である、請求項37に記載の方法。
- 対象における癌の進行を査定する方法であって、以下の工程:
該対象におけるFlightless Iの発現及び/又は活性レベルを測定する工程;
該対象におけるFlightless Iの該発現及び/又は活性レベルを、Flightless Iの発現及び/又は活性の参照レベルと比較する工程;及び
該比較に基づき、該対象における癌の該進行を査定する工程
を含む、方法。 - 前記対象が、前記癌の治療を受けている、請求項39に記載の方法。
- 前記対象におけるFlightless Iの発現及び/又は活性レベルが、Flightless Iの発現及び/又は活性の前記参照レベルよりも高い場合は、前記対象における癌の前記進行を示す、請求項39又は請求項40に記載の方法。
- Flightless Iの前記発現及び/又は活性レベルが、前記対象から得られる試料で測定される、請求項39から41のいずれか1項に記載の方法。
- Flightless Iの前記発現レベルを測定する工程が、Flightless IのRNA又はタンパク質のレベルを測定することを含む、請求項39から42のいずれか1項に記載の方法。
- 前記Flightless IのRNAはFlightless IのmRNAである、請求項43に記載の方法。
- 前記癌が、皮膚癌、結腸直腸癌、及び肺癌からなる群より選択される、請求項39から44のいずれか1項に記載の方法。
- 前記皮膚癌が、扁平上皮癌である、請求項45に記載の方法。
- 対象において癌を治療又は予防するのに有用な候補治療剤をスクリーニングする方法であって、該方法が、Flightless Iの発現及び/又は活性レベルを低下させる活性について該候補治療剤をアッセイする工程を含み、該方法において、Flightless Iの該発現及び/又は活性レベルを低下させる作用剤が、該対象において癌を治療又は予防するのに有用な候補治療剤である、方法。
- Flightless Iの前記発現レベルを測定する工程が、Flightless IのRNA又はタンパク質のレベルを測定することを含む、請求項47に記載の方法。
- 前記Flightless IのRNAが、Flightless IのmRNAである、請求項48に記載の方法。
- 前記癌が、皮膚癌、結腸直腸癌、及び肺癌からなる群より選択される、請求項47から49のいずれか1項に記載の方法。
- 前記皮膚癌が、扁平上皮癌である、請求項50に記載の方法。
- 対象において癌を治療又は予防するのに用いられる薬学的組成物であって、Flightless Iの発現及び/又は活性を低下させる作用剤を有効量で含む、組成物。
- 前記作用剤が、薬物、小分子、核酸、オリゴヌクレオチド、オリゴペプチド、ポリペプチド、タンパク質、酵素、多糖、糖タンパク質、ホルモン、受容体、受容体に対するリガンド、補因子、アンチセンスオリゴヌクレオチド、リボザイム、低分子干渉RNA、マイクロRNA、低分子ヘアピン型RNA、脂質、アプタマー、ウイルス、及び抗体又はその抗原結合部分からなる群のなかの1種又は複数より選択される、請求項52に記載の薬学的組成物。
- 前記作用剤が、Flightless Iに対する中和抗体、又はその抗原結合部分である、請求項52又は請求項53に記載の薬学的組成物。
- 前記作用剤が、Flightless I結合タンパク質である、請求項52又は請求項53に記載の薬学的組成物。
- 前記Flightless I結合タンパク質が、FLAP−1である、請求項55に記載の薬学的組成物。
- 前記癌が、皮膚癌、結腸直腸癌、及び肺癌からなる群より選択される、請求項52から56のいずれか1項に記載の薬学的組成物。
- 前記皮膚癌が、扁平上皮癌である、請求項57に記載の薬学的組成物。
- 対象において癌を診断する、対象が癌を発生しやすいかどうかを判定する、又は対象における癌の進行を査定するキットであって、該対象におけるFlightless Iの発現及び/又は活性レベルを測定する手段を含む、キット。
- 前記対象におけるFlightless Iの発現及び/又は活性レベルがFlightless Iの発現及び/又は活性の参照レベルよりも高い場合は、前記対象に癌が存在すると診断されるか、前記対象が癌を発生しやすいことを示しているか、前記対象で癌が進行していることを示す、請求項59に記載のキット。
- Flightless Iの前記発現及び/又は活性レベルが、前記対象から得られる試料で測定される、請求項59又は請求項60に記載のキット。
- Flightless Iの前記発現レベルを測定することが、Flightless IのRNA又はタンパク質のレベルを測定することを含む、請求項59から61のいずれか1項に記載のキット。
- 前記Flightless IのRNAが、Flightless IのmRNAである、請求項62に記載のキット。
- 前記癌が、皮膚癌、結腸直腸癌、及び肺癌からなる群より選択される、請求項59から63のいずれか1項に記載のキット。
- 前記皮膚癌が、扁平上皮癌である、請求項64に記載の薬学的組成物。
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