JP2022022296A - ホスファチジルイノシトール-3-キナーゼ経路バイオマーカー - Google Patents
ホスファチジルイノシトール-3-キナーゼ経路バイオマーカー Download PDFInfo
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Abstract
Description
特定の実施形態では、例えば以下が提供される:
(項目1)
対象において乳癌を治療する方法であって、
a)対象からサンプルを得るステップ、
b)PIK3CA遺伝子増幅、PIK3CAの変異、およびPTENタンパク質発現の減少の1つまたは複数の存在または不在を検出するステップ、ならびに
pan-ErbBチロシンキナーゼ阻害剤を対象に投与することによって、PIK3CA遺伝子増幅、PIK3CAの変異、およびPTENタンパク質発現の減少の1つまたは複数の存在に関して陽性である対象を治療するステップを含む方法。
(項目2)
pan-ErbBチロシンキナーゼ阻害剤が、不可逆性であり、PIK3CAがErbBの細胞内部分に結合するのを妨げる、項目1に記載の方法。
(項目3)
不可逆性pan-ErbBチロシンキナーゼ阻害剤が、ネラチニブである、項目2に記載の方法。
(項目4)
PIK3CA遺伝子の変異が、エクソン9において、成熟タンパク質配列の542位でEがKで置換されている点変異、アミノ酸545でEがKまたはDで置換されている点変異、およびエクソン20において、成熟タンパク質配列のアミノ酸1047でHがRで置換されている点変異の1つまたは複数を含む、項目1から3のいずれかに記載の方法。
(項目5)
PIK3CA遺伝子の変異を検出する方法が、ポリメラーゼ連鎖反応(PCR)アッセイ、またはPIK3CA遺伝子に特異的な核酸プローブによる直接核酸配列決定もしくはハイブリダイゼーションを含む、項目1から4のいずれかに記載の方法。
(項目6)
PTEN発現の検出が、逆相タンパク質アレイ、ウェスタンブロッティング、半定量的または定量的免疫組織化学(IHC)法の1つまたは複数を含む、項目1から5のいずれかに記載の方法。
(項目7)
対象がPIK3CA遺伝子増幅、PIK3CAの変異、およびPTENタンパク質発現の減少の1つまたは複数の存在に関して陽性である場合、対象に1種または複数の組成物または療法:手術、放射線、またはレトロゾール(Femara)、アナストロゾール(Arimidex)、フルベストラント(Faslodex)、およびエキセメスタン(Aromasin)を含めたアロマターゼ阻害剤;ゴセレリン(Zoladex);ドキソルビシン(Adriamycin)、エピルビシン(Ellence)、およびリポソーム化ドキソルビシン(Doxil)を含めたアントラサイクリン;ドセタキセル(Taxotere)、パクリタキセル(Taxol)、およびタンパク質結合パクリタキセル(Abraxane)、シクロホスファミド(Cytoxan)を含めたタキサン;カペシタビン(Xeloda)および5フルオロウラシル(5FU);ビノレルビン(Navelbine);ゲムシタビン(Gemzar);トラスツズマブ(Herceptin)、ラパチニブ、BIBW2992、PI3K阻害剤(たとえば、XL147、PX-866)、mTOR阻害剤(たとえば、テムシロリムス、エベロリムス)、およびデュアルPI3K-mTOR阻害剤(たとえば、BEZ235)の1種または複数から選択される追加の化学療法剤を投与するステップをさらに含む、項目1から6のいずれかに記載の方法。
(項目8)
対象のサンプルが、PIK3CA遺伝子増幅、PIK3CAの変異、およびPTENタンパク質発現の減少に関して陰性である場合、対象にトラスツズマブを投与する、項目1に記載の方法。
(項目9)
乳癌を有する対象がネラチニブによる治療の候補であるかどうかを判定する方法であって、
a)対象からサンプルを得るステップ、
b)PIK3CA遺伝子増幅の存在または不在を検出するステップを含み、
対象がPIK3CA遺伝子増幅、PIK3CAの変異、およびPTENタンパク質発現の減少の1つまたは複数の存在に関して陽性である場合、
対象をpan-ErbBチロシンキナーゼ阻害剤による治療の候補として同定する方法。
(項目10)
pan-ErbBチロシンキナーゼ阻害剤が、不可逆性であり、PIK3CAがErbBの細胞内部分に結合するのを妨げる、項目9に記載の方法。
(項目11)
不可逆性pan-ErbBチロシンキナーゼ阻害剤が、ネラチニブである、項目10に記載の方法。
(項目12)
PIK3CA遺伝子の変異が、エクソン9において、タンパク質配列の542位でEがKで置換されている点変異、エクソン9において、アミノ酸545でEがKまたはDで置換されている点変異、およびエクソン20において、アミノ酸1047でHがRで置換されている点変異から選択される、項目9から11のいずれかに記載の方法。
(項目13)
PIK3CA遺伝子の変異の検出が、ポリメラーゼ連鎖反応(PCR)アッセイ、直接PIK3CA遺伝子配列決定、患者のサンプルから生じるcDNAの配列決定を含む、項目9から12のいずれかに記載の方法。
(項目14)
PTEN発現の検出が、逆相タンパク質アレイ、ウェスタンブロッティング、半定量的または定量的IHCの1つまたは複数を含む、項目9から13のいずれかに記載の方法。
PI3K経路異常は、乳癌患者の診断時に著しい割合で存在し、これらは標準的療法に対するデノボ耐性機序であることをデータは示している。重要なことに、新規な標的療法(pan-ErbB阻害剤など)の導入は、一部の標準的療法に対する感受性を回復させる可能性がある。この種のバイオマーカー戦略のコンセプトは、標準的治癒療法に耐性であることが予測される患者の生物学的サブセットを同定することであり、新規な経路阻害剤の追加または代替は、その耐性機序を克服することによって、より高い治療有効性を示すことが予期されよう。たとえば、Her2+乳癌において、PI3K経路活性化は、トラスツズマブに対する耐性を予測する(12~15)。標準的なトラスツズマブ療法に反応することが予測される患者(「PI3Kオフ」)および臨床反応を得るために新規な経路阻害剤(たとえば、「PI3Kオン」の設定でpan-ErbB阻害剤)による治療を必要とする可能性のある患者を同定するために、患者の2つのサブセットを識別する(たとえば、「PI3Kオン」および「PI3Kオフ」)PI3K経路活性化のバイオマーカーが用いられる(49)。
経路活性化をもたらすPIK3CA遺伝子の原発性乳癌サンプルで観察される既知の遺伝子事象は、エクソン9もしくは20のホットスポット変異、遺伝子増幅、または両方の組合せからなる。
PTEN消失は、典型的に短縮型タンパク質を産生し得る変異に起因するC末端タンパク質エピトープを認識する抗体を用い、標準的なIHC手法を使用して臨床で日常的に研究されてきた。IHCによる既知の遺伝子消失事象とPTEN発現との間の一致と不一致の様々な例が文献に存在し、これは基礎にある生物学の解釈にいくつかの課題を生じ得る(16~17)。遺伝子損傷を有する患者の割合とタンパク質レベルの低下した患者との間の不一致に関して、可能性のあるいくつかの説明が存在する。理論に縛られるものではないが、IHC法は定量的または半定量的であることができ、解釈の相違は異なる結果を導き出すことがある。IHC法は、すべての種の全長タンパク質(機能性または機能不全)を検出し、タンパク質レベルの「低減」は、不安定化変異、miRNA発現、または共発現安定化タンパク質に由来する可能性があるのに対し、PTENタンパク質の完全補体はホスファターゼドメインの点変異によって認められることがある(18~19)。
PIK3CA遺伝子の変異
PIK3CA遺伝子(クラスIAPI3K複合体のp110αサブユニットをコードする)活性化変異が、乳癌、卵巣癌、肺癌、食道癌、子宮内膜癌、および甲状腺癌を含む、いくつかのヒト悪性腫瘍で見出されている。
PIK3CA遺伝子の増幅
PIK3CA遺伝子(遺伝子座3q26.3)もいくつかの腫瘍において増幅を受けることが示されており、機能獲得型変異と同様に、増幅は予後不良と相関する(21~24)。PIK3CA増幅は、卵巣癌および子宮内膜癌におけるPI3K経路活性化の重要な機序の1つであり、これらの患者では、増幅は遺伝子量の増大および経路活性の増大をもたらし、標準的療法に対する耐性および予後不良と相関する(21、22、25、26)。PIK3CA増幅は、乳癌ではそれほど頻繁には観察されない。初期診断サンプルにおいて、8.7%の患者が、3q26(この遺伝子座のPIK3CA)で染色体増加を有することが見出され、それらの患者の半数はPIK3CA変異も保有していた(27)。発現プロファイリングによって基底サブタイプと同定された乳癌サンプル群で、高レベルの増幅が観察された(28)。乳癌細胞株はPIK3CA増幅を保有することが見出され、PIK3CA遺伝子の増幅と変異の共存は、Aktリン酸化の増強によって測定される経路活性化の増大をもたらす。
PTEN発現
腫瘍抑制因子PTENは、PI3Kシグナル伝達複合体に対して抑止(または「ブレーキ」)として機能する、二重特異性ホスファターゼ(脂質およびタンパク質)である。PTENは、PIP3からPIP2への脱リン酸化を媒介して、PDK1およびAkt/PKBの膜結合部位を除去し、それによってPI3Kの活性に拮抗する。PTEN遺伝子(遺伝子座10q23)は、乳癌、脳癌、子宮内膜癌、腎臓癌、および前立腺癌を含む、いくつかのヒト悪性腫瘍で不活性化されている(29~32)。PTENの不活性化は、疾患の進行および予後不良と相関しており、腫瘍形成における重要な役割が示唆される(16、33~34)。実験系において、PTENの不活性化は、抑止されないAkt/PKB活性化を引き起こし、続いてアポトーシスの阻害によって腫瘍形成表現型をもたらすことが示されているのに対して、PTEN-null系でのPTEN発現の回復は、腫瘍形成表現型の消失を招く(32、35)。抑止されないAkt/PKB活性は、アポトーシスの阻害、細胞成長、および増殖の増強を引き起こす[36]。
ネラチニブ療法の患者の選択
乳癌を有する患者からサンプルを得る。このサンプルを、PIK3CA遺伝子増幅、PIK3CAの変異、およびPTENタンパク質発現の減少の1つまたは複数の存在または不在に関して分析する。これら(PIK3CA遺伝子増幅、PIK3CAの変異、およびPTENタンパク質発現の減少)の1つまたは複数の存在によって、患者は「PI3Kオン」である腫瘍を有すると指定される。患者が「PI3Kオン」と指定された場合、その患者はネラチニブで治療される。本明細書では、ネラチニブまたは併用治療に伴う任意の臨床的利益を、標準的治療処置群で認められた利益と比較することができる。これは、各患者群を個別に比較するか、または所与の処置に関して、線形回帰モデルを用いて各患者群間を比較することによって行うことができる。これらの比較によって、(おそらく腫瘍のある程度の経路「依存性」のため)標準的治療よりネラチニブが実質的な改善を示す集団を同定することができる。
患者選択のための予測バイオマーカーとしてのPI3K経路活性化:臨床における統計的考察
臨床試験に本発明のバイオマーカー戦略を組み入れるための仮定は、特定の薬物または薬物の組合せに対して、比較薬剤または標準的治療より優れた臨床的に有意な反応を有することが予期される患者が予め選択されることである。無作為化臨床試験では、選択は治療剤の基礎にある生物学に基づくものであるため、この手法によって、実験群の反応者に関して患者集団が増強されよう。対照的に、純粋に好ましい反応に関して患者集団が増強されると、実験群およびコントロール群の両方がより好ましい結果を有するため、無作為化試験の結果に影響を及ぼさない。さらに、将来の試験において、腫瘍の基礎となる生物学を用いるそのような患者選択手法はまた、それらの患者の腫瘍が特定の薬物または併用治療に対して耐性であることが予測され、所与の試験から除外される患者に、代替となる合理的な治療選択肢を提供する可能性がある。たとえば、PI3K活性化がトラスツズマブ耐性のマーカーであることがわかっているため(12、14、48)、チロシンキナーゼ阻害剤類の薬剤(たとえば、不可逆性pan-ErbB阻害剤、ネラチニブ、または可逆性Her1/Her2阻害剤、ラパチニブ)などの別の治療剤を利用できることが最適であろう(49)。
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48.Yang H, Kong W, He Lら(2008)「ヒト卵巣癌のマイクロRNA発現プロファイリング:miR-214はPTENを標的化することによって細胞生存およびシスプラチン耐性を誘発する(MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN)」Cancer Research 68:425-433.
49.O'Brien Nら(2010)「活性化ホスホイノシチド3-キナーゼ/AKTシグナル伝達はトラスツズマブ耐性を付与するが、ラパチニブ耐性は付与しない(Activated Phosphoinositide 3-Kinase/AKT Signaling Confers Resistance to Trastuzumab but not Lapatinib)」Mol Cancer Ther 9(6):1489-1502
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HUE061640T2 (hu) | 2009-04-06 | 2023-07-28 | Wyeth Llc | Gyógykezelési rendszer mellrákhoz neratinib alkalmazásával |
CN107441058A (zh) | 2009-11-09 | 2017-12-08 | 惠氏有限责任公司 | 包衣药物球状体及消除或减少病症如呕吐和腹泻的用途 |
EP2736325B1 (en) * | 2011-07-28 | 2018-10-10 | F.Hoffmann-La Roche Ag | Pik3ca h1047r knock-in non-human animal breast cancer model |
US9376715B2 (en) | 2011-12-09 | 2016-06-28 | Roche Molecular Systems, Inc | Methods for detecting mutations in the catalytic subunit of the phosphoinositol-3 kinase (PIK3CA) gene |
NZ702244A (en) * | 2012-06-08 | 2017-06-30 | Hoffmann La Roche | Mutant selectivity and combinations of a phosphoinositide 3 kinase inhibitor compound and chemotherapeutic agents for the treatment of cancer |
CN105274188A (zh) * | 2014-05-29 | 2016-01-27 | 北京雅康博生物科技有限公司 | Pik3ca基因突变检测试剂盒 |
CA2985894A1 (en) * | 2015-05-15 | 2016-11-24 | Memorial Sloan-Kettering Cancer Center | Use of phosphoinositide 3-kinase inhibitors for treatment of vascular malformations |
US9953133B2 (en) | 2015-06-03 | 2018-04-24 | General Electric Company | Biological data annotation and visualization |
US10672505B2 (en) | 2015-06-03 | 2020-06-02 | General Electric Company | Biological data annotation and visualization |
US9607375B2 (en) * | 2015-06-03 | 2017-03-28 | Eileen B. Gallagher | Biological data annotation and visualization |
KR20190054826A (ko) * | 2017-11-14 | 2019-05-22 | 한미약품 주식회사 | 암의 포지오티닙 치료에 대한 반응을 나타내는 바이오마커 및 그의 용도 |
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US8715665B2 (en) * | 2007-04-13 | 2014-05-06 | The General Hospital Corporation | Methods for treating cancer resistant to ErbB therapeutics |
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