JP6060164B2 - 過剰増殖性疾患、好ましくはp53機能欠損の治療に用いるためのCIP2Aサイレンシング剤を含む併用薬剤 - Google Patents
過剰増殖性疾患、好ましくはp53機能欠損の治療に用いるためのCIP2Aサイレンシング剤を含む併用薬剤 Download PDFInfo
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Description
本発明は、CIP2A遺伝子サイレンシングが、特定の低分子化学療法剤のアポトーシス誘導活性に対してp53がん調節タンパク質機能について危険にさらされたがん細胞を感作する、という驚くべき発見に基づく。CIP2A遺伝子のサイレンシング及びその化学療法剤の投与の併用は、p53機能が阻害されるようになった細胞におけるアポトーシス及び/又はその他のタイプの細胞死のレベルで、付加的な、又は相乗的な増加を生じた。他方、本発明は変異p53発現CIP2A陰性リンパ腫細胞が化学療法剤での単独療法に対してより感作的であることを示す。したがって、一つの側面では、本発明はCIP2A欠損の療法及び化学療法剤の組合せを提供し、一方でその他の側面では、本発明は患者サンプルのCIP2A及びp53状態を検出することによる化学療法剤に対するがん患者の階層化方法を提供する。
p53変異を発現しているヒト由来グリオーマがん細胞T98G細胞をSCR siRNA(25nM)又はCIP2A siRNA(配列番号2;25nM)のいずれかでトランスフェクトした。48時間後、siRNAを含む培地を図1に示す濃度で化学療法剤を含む培地に置換した。CIP2A阻害と標準化学療法剤を組み合せたものが、SCR siRNA又は化学療法剤単独のいずれかにより処理された細胞と比較した際に、アポトーシスをより強く誘導するかどうかを検証するため、細胞中のアポトーシス誘導の検出に用いるカスパーゼ3/7活性(カスパーゼ3/7グロ アッセイ、プロメガ)を、製造者の指示に従って48時間後に計測した。図1に示す結果は、CIP2A siRNA単独ではアポトーシスを誘導しないことを示す。しかしながら、CIP2A siRNAとラパチニブ、スニチニブ、H-7、バンデタニブ、シスプラチン、パクリタキセル、テモゾロミド、タンズチニブ又はインドール−3−カルビノールのいずれかを組み合せたものが、CIP2A siRNA単独で処理した細胞と比較して、T98G細胞におけるアポトーシスの誘導を明確に増強した。
野生型p53機能がHPV18 E6により鈍化されているヒト由来子宮頸がん細胞HeLa細胞をSCR siRNA(25nM)又はCIP2A siRNA(配列番号6;25nM)のいずれかでトランスフェクトした。72時間後、siRNAを含む培地を図2に示す濃度で化学療法剤を含む培地に置換した。SCR siRNA又は化学療法剤単独のいずれかで処理した細胞と比較したとき、CIP2A阻害と標準化学療法剤を組み合せたものが細胞の生存度をより強く減少させるかどうかを検証するため、製造者の指示に従って48時間後にCTGアッセイ(プロメガ)を用いた。図2に示す結果はCIP2A siRNA単独では細胞の生存度を減少させることについて効果がないことを示す。しかしながら、CIP2A siRNAとラパチニブ、PARPi(DPQ)、インドール−3−カルビノール、NU−7441、ラパマイシン、S31−201、TGX−221、トリコスタチンA、ゲムシタビン、又はPKC−412を組み合せたもののいずれもが、CIP2A siRNA単独で処理した細胞と比較して細胞生存度がより強く減少し、CIP2Aの阻害がこれらの化学療法剤に対してHeLa細胞を感作したことを表す。
p53変異を発現しているマウス一次リンパ腫細胞系をEmu−mycマウス系統と交雑させたCIP2A野生タイプ(CIP2A+/+)又はCIP2A欠損(CIP2A−/−)マウスの脾臓から得た。細胞を96穴プレートに播種し、「正常増殖」培地を、図3に示す濃度で化学療法剤を含む培地に置換する前に、24時間定着させた。CIP2A発現がん細胞と比較して、CIP2A欠損がん細胞が化学療法剤に対して感作されることを示す場合を検証するために、細胞中のアポトーシス誘導を計測するために用いられるカスパーゼ3/7活性(カスパーゼ3/7グロ アッセイ、プロメガ)を、製造者の指示に従って、48時間後に計測した。図3に示す結果は、CIP2A発現細胞と比較して、様々な化学療法剤(例えば、ラパチニブ、PARPi(DPQ)、PKC−412、タンズチニブ、テモゾロミド、パクリタキセル、NU−7441、TGX−221又はS31−201)で処理したときに、極めて低いCIP2A発現レベル(CIP2A−/−)を発現するリンパ腫細胞でアポトーシスがより強く誘導されることを示す。
p53変異を発現しているマウス一次リンパ腫細胞系をEmu−mycマウス系統と交雑させたCIP2A野生型(CIP2A+/+)又はCIP2A欠損(CIP2A−/−)マウスの脾臓から得た。細胞を96穴プレートに播種し、「正常増殖」培地を図4に示す濃度で化学療法剤を含む培地に置換する前に24時間定着させた。CIP2A発現細胞と比較して、CIP2A欠損がん細胞を化学療法剤で処理することにより細胞生存度が減少するかどうかを検証するために、CTGアッセイ(プロメガ)を、製造者の指示に従って、48時間後に試みた。図4に示す結果は、CIP2A発現細胞と比較して、ラパチニブ、PARPi(DPQ)、H−7、タンズチニブ、PKC−312、ラパマイシン、トリコスタチンA、S31−201又はTGX−221を含む様々な化学療法剤で処理した極めて低いCIP2Aレベル(CIP2A−/−)を発現しているリンパ腫細胞で細胞生存度がより低く減少していることを示す。
p53変異を発現するヒト由来胃がん細胞MKN28細胞をSCR siRNA(25nM)又はCIP2A siRNA(配列番号6;25nM)のいずれかでトランスフェクトした。48時間後、siRNAを含む培地は図5に示す濃度の化学療法剤を含む培地に置換した。SCR siRNA又は化学療法剤単独のいずれかで処理した細胞と比較したときに、CIP2A阻害と標準化学療法剤を組み合せたものがアポトーシスをより強く誘導するかどうかを検証するために、細胞中のアポトーシス誘導を測定するために用いるカスパーゼ3/7活性(カスパーゼ3/7グロ アッセイ、プロメガ)を、製造者の指示に従って48時間後に計測した。図5に示す結果は、SCR siRNA単独で処理したMKN28細胞と比較して、CIP2A siRNA単独でアポトーシスを誘導したことを示す。しかしながら、アポトーシスのレベルはCIP2A siRNAとH−7、バンデタニブ、シスプラチン、パクリタキセル、テモゾロミド、ゲムシタビン、PKC−412、インドール−3−カルビノール及びタンズチニブを含む様々な化学療法剤とを組み合せたときに明らかに増強した。
野生型p53を発現しているヒト由来乳がん細胞MCF−7細胞を、SCR siRNA(25nM)又はCIP2A siRNA(配列番号2;25nM)のいずれかでトランスフェクトした。48時間後、siRNAを含む培地を図6に示す濃度で化学療法剤を含む培地に置換した。CIP2A阻害と標準化学療法剤とを組み合せるとSCR siRNA又は化学療法剤のいずれか単独で処理した細胞と比較してアポトーシスを有意に誘導するかどうかを検証するために、細胞中のアポトーシス誘導を測定するために用いるカスパーゼ3/7活性(カスパーゼ3/7グロ アッセイ、プロメガ)を製造者の指示に従って48時間後に測定した。図6に示す結果は、CIP2A siRNA単独ではSCR siRNA単独で処理したMCF−7細胞と比較した際にアポトーシスを誘導しなかったことを示す。同様に、CIP2A siRNAと様々な化学療法剤を組み合せても、野生型のp53を発現するそれらの細胞ではアポトーシスを誘導しなかった。
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Claims (14)
- p53機能欠損細胞を含む過剰増殖性障害の治療に医薬として用いるための、
siRNA分子、DsiRNA分子、人工miRNA前駆体、shRNA分子、アンチセンスオリゴヌクレオチド、及びリボザイムからなる群から選択される少なくとも1種のCIP2Aサイレンシング剤、及び
PKC−412、PARP阻害剤III、インドール−3−カルビノール、シスプラチン、ラパマイシン、TGX−221、NU−7441、S31−201、及びゲムシタビンからなる群から選択される化合物を組合せて含む医薬。 - 前記CIP2Aサイレンシング剤が、配列番号1から25、及び配列番号1から25と少なくとも80%の配列相同性を有し、そのCIP2A活性を保持している配列からなる群から選択される核酸配列を含む請求項1記載の使用のための医薬。
- 乾癬、心筋肥大、良性腫瘍、固形がん、及び血液がんからなる群から選択される過剰増殖性疾患の処置に用いるための請求項2に記載の医薬。
- 前記固形がんが、頭頸部扁平上皮がん、大腸がん、胃がん、乳がん、卵巣がん、前立腺がん、子宮頸がん、食道がん、肺がん、肝がん、脳がん、神経膠腫、星状細胞腫、及び膠芽細胞腫からなる群から選択され、及び前記血液がんが、急性及び慢性T細胞及びB細胞白血病及びリンパ腫からなる群から選択される請求項3の使用のための医薬。
- 請求項1から4のいずれか一項に記載の組合せ及び少なくとも一つの薬学的に許容可能な担体を含む医薬組成物。
- p53機能が欠損している過剰増殖性細胞を化学療法剤に対して感作させる方法であって、siRNA分子、DsiRNA分子、人工miRNA前駆体、shRNA分子、アンチセンスオリゴヌクレオチド、及びリボザイムからなる群から選択される少なくとも1種のCIP2Aサイレンシング剤、及び、PKC−412、PARP阻害剤III,インドール−3−カルビノール、シスプラチン、ラパマイシン、TGX−221、NU−7441、S31−201及びゲムシタビンからなる群から選択される化合物を投与して、そのような感作を必要とするヒト又は動物対象におけるCIP2A遺伝子をサイレンシングすることによる、上記方法。
- p53機能が欠損している細胞を含む過剰増殖性疾患の治療を必要とするヒト又は動物対象における該疾患を治療するための、請求項5に記載の医薬組成物であって、siRNA分子、DsiRNA分子、人工miRNA前駆体、shRNA分子、アンチセンスオリゴヌクレオチド、リボザイムからなる群から選択される少なくとも1種のCIP2Aサイレンシング剤、及び、PKC−412、PARP阻害剤III、インドール−3−カルビノール、シスプラチン、ラパマイシン、TGX−221、NU−7441、S31−201及びゲムシタビンからなる群から選択される化合物を、併用して、同時に又は逐次に該対象に投与することによる、上記医薬組成物。
- 前記CIP2Aサイレンシング剤は、配列番号1から25、及び前記配列番号1から25に少なくとも80%の配列相同性を有し、そのCIP2Aサイレンシング活性を保持している配列からなる群から選択される核酸配列を含む請求項5に記載の医薬組成物。
- 乾癬、心筋肥大、良性腫瘍、固形がん、及び血液がんからなる群から選択される過剰増殖性疾患の処置に用いるための請求項5に記載の医薬組成物。
- 固形がんが、頭頸部扁平上皮がん、大腸がん、胃がん、乳がん、卵巣がん、前立腺がん、子宮頸がん、脳がん、神経膠腫、星状細胞腫、及び膠芽細胞腫からなる群から選択される、請求項9に記載の医薬組成物。
- がん療法を必要とする対象のためのがん療法を選択する方法であって、該対象から得られる試料中のCIP2A及びp53発現及び/又はタンパク質活性を評価し、及びサンプルがCIP2A発現及び/又は活性が陰性であり、p53活性が欠損である対象のために少なくとも1種の化学療法剤による単一療法を選択し、及びサンプルがCIP2A発現陽性であり、p53活性欠損である対象のための療法として請求項1に記載の組合せを選択することを含む上記方法。
- 対象が、乾癬、心筋肥大、良性腫瘍、固形がん、及び血液がんからなる群から選択される過剰増殖性疾患で規定される疾患を被る対象である、請求項11に記載の方法。
- 固形がんが、頭頸部扁平上皮がん、大腸がん、胃がん、乳がん、卵巣がん、前立腺がん、子宮頸がん、脳がん、神経膠腫、星状細胞腫、及び膠芽細胞腫からなる群から選択される、請求項12に記載の方法。
- 請求項11に記載の方法を実行するための試薬を含むキット。
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