JP6684857B2 - ダイナミックbh3プロファイリング - Google Patents
ダイナミックbh3プロファイリング Download PDFInfo
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- JP6684857B2 JP6684857B2 JP2018109490A JP2018109490A JP6684857B2 JP 6684857 B2 JP6684857 B2 JP 6684857B2 JP 2018109490 A JP2018109490 A JP 2018109490A JP 2018109490 A JP2018109490 A JP 2018109490A JP 6684857 B2 JP6684857 B2 JP 6684857B2
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Description
本出願は、2012年9月19日に出願された仮出願USSN61/702,967に対する優先権およびその利益を主張するものであり、その内容は全体として参照により本明細書中に組み込まれる。
本発明は、一般に、化学療法および特に標的療法に対する反応を予測する方法に関する。
より多くの標的療法が、種々のタイプのがんに対して承認されるにつれて、これらの療法が、それらから最大の利益を得るであろう患者に対して進められ得るように、予測バイオマーカーに対するニーズが高まりつつあるが、残念なことに、がん治療に利用可能なバイオマーカーは充分ではない。近年、チロシンキナーゼインヒビター(TKI)の開発によって、進行疾患を患う患者における処置が改善された。例えば、EGFRにおける変異を検出することは、EGFRインヒビターを用いる初期治療のためのバイオマーカーとして、首尾よく使用されている。多くの標的薬剤は、遺伝子予測マーカーを欠いている。さらに、これらの薬に対する耐性は頻繁に出現しており、その耐性機序の多様性を考えると、この耐性の出現の次にどのような処置を施すのが最も良いかが、しばしば不明である。本発明は、より良好な薬が患者に当てがわれ得るようにするために、治療に対する反応を予測する方法を提供する。
各種の態様において、本発明は化学療法に対する反応を予測する方法を提供する。
本発明は、がん細胞が死に対してどの程度「準備されている」のかを測定するものとしてもまた知られている、がん細胞がプログラム細胞死(すなわち、アポトーシス)の閾にどの程度近いのかを測定する技術、の発見に一部基づく。本発明の方法は、プログラム細胞死の閾にがん細胞をより近づける(プライミングを最も増大させる)薬物の同定を可能にする。本発明は、個々の臨床がんサンプルに適用され得ることによって、プログラム細胞死の閾にそのサンプル中の細胞を最も近づける、その個々のサンプル用のそれらの薬物を容易に同定することができる。そのように同定された薬物は、サンプルが由来した患者に臨床的利益を提供する可能性が最も高い。したがって、本発明は、個々のがん患者に対する個別化治療の方法を提供する。
アポトーシス促進性のBCL−2のBH3ドメインペプチドは、長さ195アミノ酸未満、例えば、長さ150、100、75、50、35、25または15アミノ酸以下等である。アポトーシス促進性のBCL−2のBH3ドメインペプチドは、Bcl-2 interacting mediator of cell death(BIM);BH3 interacting domain death agonist(BID);Bcl-2-associated death promoter(BAD);NOXA;p53 up-regulated modulator of apoptosis(PUMA);Bcl-2-modifying factor(BMF)およびharakiri(HRK)を含む。BH3ドメインペプチドは、配列NH2−XXXXXXXXXXLXXXXDXXXX−COOH(配列番号16)を(完全または部分的に)含むペプチドを含む。本明細書中において使用されるXは、いずれのアミノ酸であってもよい。あるいは、BH3ドメインペプチドは、配列番号16の、少なくとも5個、6個、7個、8個、9個、15個またはそれより多いアミノ酸を含む。
例えば、アポトーシス促進性のBCL−2のBH3ドメインペプチドは、表1に表した配列番号1〜14の配列を含む。PUMA2A(配列番号15)は陰性対照である。
本発明はその詳細な説明と併せて記載されているが、前記載は、説明を目的としているのであって、添付のクレームの範囲によって定義される本発明の範囲を限定することを目的としていない。他の側面、利点および変更は、以下のクレームの範囲内である。
Claims (22)
- 治療剤に対するin vivoでの細胞の応答を予測する方法であって、
a)初発の患者のがん細胞を含み、試験治療剤に曝露された試験細胞集団を、アポトーシス促進性のBH3ドメインペプチドにin vitroで接触させること;
b)初発の患者のがん細胞を含み、試験治療剤に暴露されていない対照細胞集団を、アポトーシス促進性のBH3ドメインペプチドにin vitroで接触させること;
c)試験細胞集団における、BH3ドメインペプチドにより誘導されるミトコンドリア外膜の透過化の量、および、対照細胞集団における、BH3ドメインペプチドにより誘導されるミトコンドリア外膜の透過化の量を測定すること;ならびに
d)試験細胞集団における、BH3ドメインペプチドにより誘導されるミトコンドリア外膜の膜透過化の量を、前記治療剤に接触させていない対照細胞集団と比較すること
を含み、対照細胞集団と比較した、試験細胞集団におけるミトコンドリア外膜透過化の上昇が、患者のがん細胞がin vivoで試験治療剤に対して感受性があることを示す、前記方法。 - 対照細胞集団と比較した、試験細胞集団におけるミトコンドリア外膜透過化の減少または無変化が、患者のがん細胞がin vivoで試験治療剤に対して耐性があることを示す、請求項1に記載の方法。
- がん細胞が血液がん細胞を含む、請求項1または2に記載の方法。
- 血液がん細胞が急性骨髄性白血病細胞を含む、請求項3に記載の方法。
- 血液がん細胞が慢性骨髄性白血病細胞を含む、請求項3に記載の方法。
- 血液がん細胞がびまん性大細胞型B細胞性リンパ腫細胞を含む、請求項3に記載の方法。
- 血液がん細胞が多発性骨髄腫細胞を含む、請求項3に記載の方法。
- がん細胞が固形腫瘍細胞を含む、請求項1または2に記載の方法。
- 固形腫瘍細胞が乳がん細胞を含む、請求項8に記載の方法。
- 固形腫瘍細胞が非小細胞肺がん細胞を含む、請求項8に記載の方法。
- 固形腫瘍細胞がメラノーマ細胞を含む、請求項8に記載の方法。
- 固形腫瘍細胞が結腸がん細胞を含む、請求項8に記載の方法。
- アポトーシス促進性のBH3ドメインペプチドに接触させる前に、試験細胞集団および対照細胞集団を透過化することをさらに含む、請求項1〜12のいずれか一項に記載の方法。
- BH3ドメインペプチドにより誘導されるミトコンドリア外膜の透過化の量が、電位差測定用の色素の発光、または、ミトコンドリア膜間腔からの分子の放出を測定することによって決定される、請求項1〜13のいずれか一項に記載の方法。
- 試験細胞集団および対照細胞集団を、電位差測定用の色素に接触させること、または、試験細胞集団および対照細胞集団を、シトクロムC、SMAC/Diablo、Omi、アデニル酸キナーゼ−2またはアポトーシス誘導因子に対する抗体に接触させることをさらに含む、請求項14に記載の方法。
- 電位差測定用の色素が、JC−1またはジヒドロローダミン123である、請求項15に記載の方法。
- アポトーシス促進性のBH3ドメインペプチドが、BID、BIM、BAD、NOXA、PUMA、BMFまたはHRKのポリペプチドのBH3ドメインに由来する、請求項1〜16のいずれか一項に記載の方法。
- アポトーシス促進性のBH3ドメインペプチドが、配列番号1〜14からなる群から選択される、請求項1〜17のいずれか一項に記載の方法。
- 試験治療剤が、化学療法剤である、請求項1〜18のいずれか一項に記載の方法。
- 化学療法剤が、標的化学療法剤である、請求項19に記載の方法。
- 試験細胞集団および対照細胞集団を、ミトコンドリア外膜透過化を測定する前に、固定することをさらに含む、請求項1〜20のいずれか一項に記載の方法。
- 試験細胞集団および対照細胞集団を、細胞内のまたは細胞外のマーカーに対する抗体に接触させることをさらに含む、請求項1〜21のいずれか一項に記載の方法。
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