JP6860476B2 - 前立腺がん治療に関する方法及び組成物 - Google Patents
前立腺がん治療に関する方法及び組成物 Download PDFInfo
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- JP6860476B2 JP6860476B2 JP2017511236A JP2017511236A JP6860476B2 JP 6860476 B2 JP6860476 B2 JP 6860476B2 JP 2017511236 A JP2017511236 A JP 2017511236A JP 2017511236 A JP2017511236 A JP 2017511236A JP 6860476 B2 JP6860476 B2 JP 6860476B2
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Description
本出願は、2014年8月25日に出願された、米国仮特許出願番号62/041,368の優先利益、2015年2月26日に出願された、米国仮特許出願番号62/120,877の優先利益、及び2015年4月17日に出願された、米国仮特許出願番号62/149,408の優先利益を主張する。各出願は、その全体を参照として、本明細書に組み入れる。
本発明は、国防総省前立腺がん研究プログラムによって与えられた、グラント番号W81XWH−12−1−0605、国立衛生研究所(NIH)によって与えられた、グラント番号P50 CA058236及びグラント番号P30 CA006973のもとで、政府援助により達成された。米国政府は、本発明に一定の権利を有する。
2015年、8月25日作成のテキストファイル名「36406_0008P1_Sequence_Listing(36406_0008P1配列リスト)」で、2015年8月25日に提出され、及び4,096バイトのサイズを有する配列リストを、参照として本明細書に組み入れる。
例示的な保存アミノ酸置換
参考文献
1.実験法
a.患者
エンザルタミド又はアビラテロンを伴う標準治療を開始した、転移性CRPCの男性を、予め登録した。患者は、組織学的に確認された前立腺腺がんを有し、血清のテストステロンが「castration levels(去勢レベル)」であるにもかかわらず(<50ng/dL、及びアンドロゲン抑制療法を継続する必要があった)進行性疾患であり、及びコンピューター断層撮影(CT)又はテクネチウム99骨スキャン上で、放射線学的転移であることが必要とされた。患者は、前立腺がんワーキング群(PCWG2)のガイドラインと一致するように、その最後の値が≧2.0ng/mLであった時から、2週間以上離れた時点で採取された血清特異抗原(PSA)の値が、≧3に上昇している必要があった(Scher,H.I.,et al.(2008)Journal of Clinical Oncology、Official Journal of the American Society of Clinical Oncology 26,1148−1159)。仮に患者が、追加の同時抗がん療法を受ける予定の場合は、除外した。化学療法以前の、代替AR指向薬での前治療は、認められていた(すなわち、エンザルタミドで治療の患者における、アビラテロンの事前使用、及びその反対)。本研究は、the Johns Hopkins University(ジョンズ ・ ホプキンス大学)IRBによって承認され、Good Clinical Practice guidelines(医薬品の臨床試験の実施に関するガイドライン)に従って実施された。患者には、書面によるインフォームドコンセントが用意された。
本研究は、AR指向薬への応答性又は耐性を予測するために、CTC(循環性腫瘍細胞)からの基準点(治療前)でのAR−V7状態の能力を評価する予測研究である。エンザルタミド又はアビラテロンの標準治療をまさに開始しようとしていた患者に承諾してもらい、次いで末梢血液CTCサンプルを、1つを基準点として、1つを臨床/生化学的応答の時点で(仮に応答が発生したら)、また、1つを臨床/放射線学的進行の時点での、最大3時点まで提供するように求めた。更に、患者に、基準点及び進行の時点で、転移性コア腫瘍生検を受けるように勧めた。エンザルタミドを、毎日160mg与え、及びアビラテロンを、毎日1000mg(日に2回のプレドニゾン5mgと共に)与えた。
商業的に入手可能な、ALERE(商標)CTC AdnaTestプラットフォーム(AdnaGen,Langenhagen,Germany)を使用して、CTC分析を行った。ProstateCancerSelectキットを使用して、CTCの単離及び濃縮を実施し、ならびに、CTCの存在を検出するための、多重化逆転写ポリメラーゼ連鎖反応(qRT−PCR)プライマー、及び完全長AR(AR−FL)ならびにARスプライス変異体7(AR−V7)を検出するように設計されたカスタムプライマーを伴う、ProstateCancerDetectキットを使用して、mRNA発現解析を行った(Hu,R.,et al.(2009)Cancer Res 69,16−22)。相対的なAR−V7転写産物量を、AR−FLに対するAR−V7の比率を計算し、決定した(Hu,R.,et al.(2009)Cancer Res 69,16−22、Watson,P.A.,et al.(2010)Proceedings of the National Academy of Sciences)。
第一終点は、任意の治療後の時点で、PSA応答(基準点からの≧50%PSA減少、≧4週間維持)に達した患者の割合であり、エンザルタミド治療の患者とアビラテロン治療の患者を分けて評価した。各患者について、最高PSA応答(基準点からの、PSA減少の最大パーセント)を決定した。
CTCと腫瘍組織間のAR−V7状態の一致を検討するために、これに同意した患者のサブ集団からの、新鮮な転移性腫瘍生検(又は解剖検体)について、AR−V7に対するqRT−PCRを実施した。更に、ホルマリン固定パラフィン包埋の転移腫瘍組織において AR−V7のmRNAを視覚化するために、及びCTCsにおけるAR−V7検出とこれを関連付けるために、RNAscopeプラットフォーム(AdvancedCell Diagnostics,Hayward,CA)を使用し、製造者の指示に従って、RNAの現場でのハイブリダイゼーション(RNA−ISH)を行った。
ラベンダー色の蓋付き採血管である標準的なBD Vacutainer(登録商標)(Becton Dickinson, Franklin Lakes, NJ)(製品#:367862)を使用して、静脈穿刺により採血し、実験室の氷上に持ち込んだ。Alere(商標)CTC AdnaTest(Alere Inc.,San Diego,CA)から提供された指示に従って、採血の2時間以内に検査処理を行った。このAdnaTestは、2つの成分/キットを伴った、CEマークされた、RNAに基づく、CTC濃縮及び検出試験である。簡単に説明すると、前立腺がん細胞を認識する抗体の組み合わせで被覆した磁気粒子を利用して、5mLの血液からCTCを濃縮するために、ProstateCancerSelect(Product No.T−1−520)キットを使用し、一方で多重化ポリメラーゼの連鎖反応(PCR)を利用して、前立腺がんのRNA転写の検出に対応したcDNAを作るために、ProstateCancerDetect(Product No.T−1−521)キットを使用した。Agilent Bioanalyzer(Agilent Technologies,Palo Alto,CA)による、PSA、PSMA、又はEGFR(非常にまれに検出される)に対するPCRシグナルの検出に基づいて、検査した各サンプルに対して、CTC細胞を作成した。AR−FL(順方向:5′−CAGCCTATTGCGAGAGAGCTG−3′SEQ ID番号:1、逆方向:5′−GAAAGGATCTTGGGCACTTGC−3′SEQ ID番号:2)及びAR−V7(順方向:5′−CCATCTTGTCGTCTTCGGAAATGTTA−3′SEQ ID番号:3、逆方向:5′− TTGAATGAGGCAAGTCAGC−CTTTCT−3′SEQ ID番号:4)に特異的なカスタムプライマーを使用して、定量的リアルタイムPCRによって、AR−FL及びAR−V7の検出及び定量化のための試験を行った。簡単に説明すると、95℃×10秒、58℃×30秒、及び72℃×30秒で39サイクルの最適条件下で、PCR反応を実行し、次いで溶融曲線解析を行った。AR−FL及びAR−V7に対する絶対転写複製数を計算するために、AR−FL及びAR−V7の既知量から標準希釈曲線を生み出した。無差別方式で、本研究に登録された各患者に対して、実験データを生み出し、週単位で、マスターデータシートに記録した。偽陽性及び偽陰性の知見を排除するために、陰性及び陽性対照を含んで、CTC検出及びAR定量化の両方に対して複数レベルで、アッセイが実行されるごとに、多数の品質管理基準を適用した。
ACD(Advanced cell Diagnostics,Hayward,CA)RNAscope 2.0 Brownキットを使用して、アンドロゲン受容体(AR)及びAR−V7を検出するために、RNAの現場でのハイブリダイゼーション(RISH)を実施した。簡単に説明すると、ホルマリン固定パラフィン包埋 (FFPE)組織又は細胞のペレット塊を、切片にし、及びそのスライドを、60℃で1時間加熱した。次いでそのスライドを、室温で20分間、キシレンを使用して脱パラフィン化し、次いで100%エタノールを使用して2回リンスした後、空気乾燥した。一連の前処理工程に続いて、その細胞を、プローブがRNA標的にアクセスできるように、プロテアーゼを使用して浸透させた。ヒトARのエクソン1(ACD401211)、又は隠れたARエクソン3配列(Hu,R.,et al.(2009)Cancer Res 69,16−22、Hu,R.,et al.(2011)The Prostate 71,1656−1667)に相応するRNAを検出するように、前置増幅器のために結合部位を形成する一連のオリゴヌクレオチド対である、ACD標的プローブをカスタム設計した。当該プローブのARのRNA標的へのハイブリダイゼーションを、40℃で2時間のオーブン中の培養によって、実行した。2回の洗浄後、そのスライドを、製造者の指示通りに、標準的なシグナル増幅工程で処理した。
1×のプロテアーゼ阻害剤(Roche,Indianapolis,IN)、及び1×のホスファターゼ阻害剤(Thermo Fisher Scientific,Rockford,IL)を補充したRIPA緩衝液(放射性免疫沈降分析緩衝液)(Cell Signaling Technology,Danvers,MA)を使用して培養した前立腺がん細胞、又は臨床検体から用意した凍結切片から、全細胞タンパク抽出物を用意した。10%のSDS−PAGEプレキャストゲル(Bio−Rad Laboratories,Hercules,CA)上での、サンプル当たり40μgの電気泳動に続いて、標準ブロットを調合し、抗AR−V7(Hu,R.,et al.(2012)Cancer Res 72,3457−3462)(1μg/mL)、抗AR(N20)(1対2000希釈)(sc−816,Santa Cruz Biotechnology,Dallas,TX)、抗PSA(C−19)(1対500)(sc−7638,Santa Cruz Biotechnology)、及び抗β−アクチン(1対5000希釈)(Sigma,St Louis,MO)と共に、一晩培養した。西洋ワサビペルオキシダーゼ(HRP)共役二次抗体との培養に続いて、HyBlot CL膜(E3022)(Denville Scientific,South Plainfield,NJ)上で、SuperSignal West Pico Chemiluminescent Substrateシステム(I−34080)(Thermo Fisher Scientific,Rockford,IL)を使用して、免疫活性帯を可視化した。
LNCaP細胞(ATCC,Manassas,VA)を、10%の牛胎児血清(FBS,Sigma-Aldrich,St.Louis,MO)と共に、RPMI1640培地(Invitrogen,Carlsbad,CA)に保持した。LNCaP95は、前述した親LNCaP細胞(Hu,R.,et al.(2012)Cancer Res 72,3457−3462)から誘導したAR−V7陽性アンドロゲン非依存性細胞株である。LNCaP95細胞は、10%の活性炭処理FBS(CSS)で補充された、フェノールレッドの無いRPMI1640培地に保持した。AR−V7におけるアンドロゲン由来の変化を解析するために、LNCaP95細胞を、R1881(NEN,Waltham,MA)又は前述の対照となるエタノール担持体(Hu,R.,et al.(2012)Cancer Res 72,3457−3462)で処理した。これら細胞株を、短い直列繰り返しDNAプロファイリングを使用して認証し(DDC Medical,Fairfield,OH)、マイコプラズマに対する陰性を検査した。
エンザルタミドでの治療の経過中に死亡した2人の患者について、研究用死体解剖を実施した。両患者は、治療前後でのCTCアッセイによる決定では、AR−V7陽性であった。前立腺腫瘍を解剖し、及急速冷凍された塊を用意した。組織学的解析に続いて、腫瘍細胞で濃縮された凍結切片を、前述の標準手順(Luo,J.,et al.(2001)Cancer Res 61,4683−4688)を使用し、その冷凍塊の手動断片化に従って用意した。十分な量の高品質な総RNAを、2つの検体(各患者から1つ)から抽出し、AR−V7(+)Met1及びAR−V7(+)Met2として、各々を標識化した。比較用で、関連するAR−V7陰性の転移性CRPCサンプルを特定するために、AR−FL及びAR−V7の発現レベルを、前述した解剖に同意した(エンザルタミド及びアビラテロンの開発以前に)男性からの、別々のCRPC検体において解析した(Hu,R.,et al.(2009)Cancer Res 69,16−22、 Aryee,M.J.,et al.(2013)Science translational medicine 5,169ra10、Liu,W.,et al.(2009)Nature medicine 15,559−565)。この検体採取から、AR−V7が陰性であるが、その他のmCRPC検体で検出されたものと同じAR−FLレベルである、2つの検体を特定した。これら2つのサンプルを、AR−V7(−)Met1及びAR−V7(−)Met2として標識化した。両サンプルを、前立腺がん細胞を濃縮するために、同じ方法で組織学的に加工した。
4つの転移性前立腺組織の検体、AR−V7(+)Met1、AR−V7(+)Met2、AR−V7(−)Met1、及びAR−V7(−)Met2を、標準的なTruSeq Stranded Total RNA Sample Prep Kitに従うRNA−Seqに供し、Illumina HiSeq 2000プラットフォーム(Illumina Inc,San Diego,CA)を使用して、配列決定した。平均で、サンプル当たり約6300万読み出しを達成した。配列を、TopHatを使用したUCSC hg19ゲノム構築に対応して並べ、変異ならびにスプライス接合を、Integrated Genome Viewer(IGV)(Robinson,J.T.,et al.(2011)Nature biotechnology 29,24−26)を利用して可視化した。HTSeq(Anders,S.,et al.(2014)HTSeq−A Python framework to work with high−throughput sequencing data.bioRxiv)を使用して、読み出し数(遺伝子発現レベル)を取得し、1000当たりの塩基対遺伝子長及び100万当たりの読み出しライブラリーサイズ(RPKM)で正規化した。この2つの条件(AR−V7(+)及びAR−V7(−))間での倍数発現変化(FC)を計算した。遺伝子を、logFCで事前ランク付けし、Gene Set Enrichment Analysis(GSEA)に供した(Subramanian,A.,et al.(2005)Proceedings of the National Academy of Sciences of the United States of America 102:15545−15550)。生及び加工の両RNA−Seqデータを、Gene Expression Omnibus(受託番号:GSE56701)に蓄積した。
エンザルタミド及びアビラテロンの群について、別々に統計分析を実施した。PSA応答の第一終点に基づき、サンプルサイズを決定した。AR−V7は、エンザルタミドで治療の患者の50%及びアビラテロンで治療の患者の50%において、基準点となるCTCサンプルから検出される、と推定した。両群において、PSA応答率を、AR−V7陽性患者では≦10%、AR−V7陰性患者では≧60%と、仮定した(Scher,H.I.,et al.(2012)New England Journal of Medicine 367,1187−1197、Ryan,C.J.,et al.(2013)New England Journal of Medicine 368,138−148)。この仮定の下で、α=0.10の両側検定を使用した場合、30人の患者(群当たり)のサンプルサイズが、PSA応答率が10%(AR−V7陽性の男性において)から60%(AR−V7陰性の男性において)における差異を検出するために、検定力85%を生み出すと、推定された。
第一に、VCaP細胞でスパイクされた正常なヒト血液からのAR−V7転写の検出(図1A)は、AR−FL及びAR−V7の両方を発現することが知られている前立腺がん細胞であることを示していた(Hu,R.,et al.(2009)Cancer Res 69,16−22)。次いで、患者のサンプルを測定した。2人の患者からの血液サンプルにおける、AR−V7の陽性及び陰性検出の実施例を示す(図1B)。その検査の妥当性を検証した後(図示せず)、サイクル数と事前に定量化されたAR−V7の連続希釈の間の関連性によって決定された、AR−V7のcDNAの≧1複製の検出に対応している、PCRの≦36サイクルでの、qRT−PCRによる当該AR−V7転写の検出を、AR−V7陽性と定義した。
2012年の12月から2013年の9月の間に、31人のエンザルタミド治療(表1)及び31人のアビラテロン治療(表2)を受けた、62人の患者を、予め登録した。エンザルタミドで治療された患者のフォローアップ期間の中央値は、5.4(1.4〜9.9の範囲)ヶ月であり、及びアビラテロンで治療された患者の場合は、4.6(0.9〜8.2の範囲)ヶ月であった。エンザルタミドで治療された患者の38.7%(12/31)及びアビラテロンで治療された患者の19.4%(6/31)は、基準CTCサンプル中に、検出可能なAR−V7のmRNAを有していた。全研究群からの検出可能なAR−V7(n=18)を有した男性において、AR−FLに対するAR−V7比率の中央値は、21.0%(1.8〜208.0%の範囲)であり(図3A)、AR−V7の検出は、AR−FLの増加した発現と関連していた(P<0.001)(図3B及び3C)。
表1
*P値は、カテゴリー変数及び連続変数の各々に対して、フィッシャーの正確確率検定及びマン・ホイットニーのU検定に基づく。
表2
*P値は、カテゴリー変数及び連続変数の各々に対して、フィッシャーの正確確率検定及びマン・ホイットニーのU検定に基づく。
表3
表4
表5
エンザルタミドにおいてPSA応答に達した患者の全割合は、32.3%(10/31人、95%CI、17.1〜51.2%)であった。エンザルタミドで治療された男性間で、PSA応答率は、AR−V7陽性患者では0%(0/12人、95%CI、0〜26.4%)、及びAR−V7陰性患者では52.6%(10/19人、95%CI、29.3〜76.1%)であった。最高PSA応答を、図4Aに描写する。線形回帰モデルにおいて、AR−V7状態は、AR−FL発現への調製後も、PSA応答に予測を示した(P<0.001)。
a.PSA−PFS
エンザルタミドで治療された男性の間では、PSA無増悪期間(PSA−PFS)は、基準点で検出可能(対検出不可能)なAR−V7転写産物(単変量 P<0.001)を持つ男性において、劣っていた(図5A)。AR−FL発現及び事前のアビラテロン使用に対して調整した、多変量コックスモデルにおいて、AR−V7の存在が、PSA−PFS(HR3.1、95%CI 1.0〜9.2、P=0.046)の個別予測を示し、AR−FLレベルがまた、PSA−PFS(HR1.4、95%CI 1.0〜1.9、P=0.051)の予測を示したが、事前のアビラテロン使用は、そうした予測を示さなかった(HR2.5、95%CI 0.4〜14.5、P=0.294)。その傾向スコア加重多変量モデルの結果を、表6に示す。
表6
表7
エンザルタミドで治療された患者の間では、臨床/放射線無増悪期間(PFS)は、基準点で検出可能AR−V7(単変量 P<0.001)を持つ男性において、劣っていた(図5C)。AR−FL発現及び事前のアビラテロン使用に対して調整した、多変量コックスモデルにおいて、AR−V7の存在が、PFS(HR3.0、95%CI 0.9〜9.6、P=0.064)の予測を示し、AR−FLレベルがまた、PFS(HR1.7、95%CI 1.1〜2.6、P=0.017)の予測を示したが、事前のアビラテロン使用は、そうした予測を示さなかった(HR2.6、95%CI 0.2〜27.6、P=0.433)。表8は、その傾向スコア加重多変量モデルを示す。
表8
表9
当該エンザルタミドで治療された群における10人の死亡(成人32%、フォローアップ期間の中央値8.4ヶ月)、及び当該アビラテロンで治療された群における5人の死亡(成人16%、フォローアップ期間の中央値9.3ヶ月)の後に、予備的な生存時間解析を実施した。OSは、当該エンザルタミド群(HR6.9、95%CI 1.7〜28.1、ログランク検定 P=0.002)(図5E)及び当該アビラテロン群(HR12.7、95%CI 1.3〜125,3、ログランク検定 P=0.006)(図5F)の両方において、基準点で検出可能(対検出不可能)なAR−V7を持つ男性において、劣っていた。各群で事象が少数のために、多変量モデルは、構築されなかった。
探索的データ解析として、全部で62人の対象者を含む組み合わせた患者集団を使用して、PSA−PFS、PFS、及びOSの、PSA応答を評価した。理論に拘束されることを望まないが、これらデータは、これらの結果におけるAR−V7状態の影響は、有意性を残していたことを示す。(図6A〜D)。
初期にAR−V7非検出であり、≧1の追加フォローアップサンプル(n=42)を伴った男性の間において、6人の患者(エンザルタミドについて4、アビラテロンについて2)はその後、一連の治療中にAR−V7陽性に転換した一方で、初期にAR−V7検出(≧1の追加フォローアップサンプルを伴う)の16人の患者全てにおいて、治療の間、AR−V7陽性を維持した。これら患者の臨床結果を、表10にまとめる。一連の治療中でのAR−V7発現レベルの変化を、図7A及び7Bにまとめる。
表10
a基準点で、AR−V7陰性であった44患者の内、42人は、少なくとも1つのフォローアップサンプルを採取され、これら男性の36人(86%)は、フォローアップでAR−V7陰性を残し(AR−V7[−]→AR−V7[−])、一方これら男性の6人(14%)は、フォローアップでAR−V7陽性に転換した(AR−V7[−]→AR−V7[+])。基準点で、AR−V7陽性であった18患者の内、16人は、少なくとも1つのフォローアップサンプルを採取され、これら男性の全ては、フォローアップでAR−V7陽性を残していた(AR−V7[+]→AR−V7[+])。これら患者の臨床結果もまた、示す。
7人の患者が、追加の組織に基づく研究に同意した。5人は、転移性腫瘍生検を受け、及び2人は、彼らの死後の研究遺体解剖を許諾した。この7人の患者の内の3人は、CTCに検出可能なAR−V7を有しており、これら3人の患者はまた、qRT−PCR及びRNA−ISH解析を使用した転移性腫瘍組織に、検出可能なAR−V7を有していた(図8)。更に、これら患者において、ウェスタンブロット解析を使用して、そのタンパク質レベルに、AR−V7(及びAR−FL)を検出した。反対に、CTCにAR−V7が検出不可能であった4人の患者は、良好な一致を示して、転移性組織におけるRNA−ISHによって検出可能なAR−V7を有していなかった。最後に、2人のAR−V7陽性患者(解剖検体)からの転移巣において、RNA−Seqを使用した、そのAR転写産物の配列解析は、耐性を説明するAR変異を特定しなかったが、両患者において、AR−V7スプライス接合の存在を確認した(図10A及び10B)。
検出可能なAR−V7を有する全ての患者において、AR−FLもまた、より高いレベルで発現され(1患者を除く)、AR−V7の増加発現は一般に、AR−FLと一体である(ただし常にではない)(図3A〜C)。一方PSA(標準的ARシグナル伝達の指標)発現は一般に、エンザルタミド/アビラテロンで治療中のAR−V7陰性患者においては、抑制され、PSA発現は、基準点で検出可能なAR−V7を有する男性からの治療後CTCサンプルにおいて、減少しなかった(図11)。理論に拘束されることを望まないが、これらのデータは、AR−FLの耐性機構の独立性、意図した薬剤標的を示唆している。更に、Gene Set Enrichment Analysis of RNA−Seqデータ(図10A、10B、及び12)による、又は一連の標準的AR制御遺伝子の標的解析(表11)による、2つのAR−V7陰性及び2つのAR−V7陽性の転移性腫瘍サンプルの全ゲノム比較では、両比較が、AR−V7陽性サンプルにおける、AR−V7駆動の転写へのシフトと一致した変化を明らかにした。
エンザルタミド及びアビラテロン、2つの新しいAR指向の療法は、CRPCの管理において有意な進歩を表す(Scher,H.I.,et al(2010)Lancet375,1437−1446、Scher,H.I.,et al(2012)New England Journal of Medicine 367,1187−1197、Ryan,C.J.et al.(2013)New England Journal of Medicine 368,138−148、de Bono,J.S.,et al.(2011)New England Journal of Medicine 364,1995−2005)。しかしながら、ある割合の男性は、これら薬剤の恩恵を受けておらず、これら薬剤への耐性に横たわる機構のより明確な理解が、そのような患者に対する代替療法(例えば、化学療法)の選択を促進するであろう。理論に拘束されることを望まないが、本明細書に提示するデータは、AR−V7が、CTCから確実に検出され、腫瘍細胞におけるAR−V7の検出が、エンザルタミド及びアビラテロンの両方への耐性に関連している可能性がある、ことを示唆している。この概念的に単純なモデルは、AR−V7が、そのARリガンド結合ドメイン(エンザルタミドの直接標的及びアビラテロンの間接標的)を欠いている一方で、リガンド非依存様式において、転写因子としての恒常活性を残しているので、生物学的に妥当性がある(Hu,R.,et al.(2009)Cancer Res 69,16−22、Guo,Z.,et al.(2009)Cancer Research 69,2305−2313)。驚くことに、本研究において、AR−V7陽性患者は、エンザルタミド又はアビラテロンに対して、いかなる大きな臨床的恩恵をも受けなかった。更に、一方でAR−V7の検出は、より高いAR−FL発現と関連しており、AR−V7の予後への影響は、AR−FLレベルの調製後も維持されていた。最終的に、アビラテロン/エンザルタミドでの事前治療が、AR−V7陽性の発生率を上げたが、AR−V7状態は、この因子の調整後の予後にも維持された。
この実施例は、タキサンへの感受性を保持しているAR−V7陽性の患者、及びAR−V7状態が、タキサンで治療された男性対エンザルタミド/アビラテロンで治療された男性において、異なる影響力を有する可能性があることを示す。
患者
本研究では、ドセタキセル又はカバジタキセルでの標準治療を開始していた、転移性CRPCの男性を登録した。患者は、組織学的に確認された前立腺腺がんを有し、血清のテストステロンが「castration levels(去勢レベル)」であるにもかかわらず(<50ng/dL)進行性疾患であり、コンピューター断層撮影(CT)又はテクネチウム99骨スキャン上で、放射線転移性であることが必要とされた。患者は、前立腺がんワーキング群(PCWG2)のガイドラインに一致するように、その最後の値が≧2.0ng/mLであった時から、2週間以上離れた時点で採取された血清PSA値が、≧3に上昇している必要があった23。仮に患者が、一連のタキサン治療中に、追加の同時抗がん療法(標準の又は治験的な)を受ける予定の場合は、除外した。カバジタキセルでの治療を開始している(そのラベルの指示に従って5)男性の間で、ドセタキセルで事前治療したように、アビラテロン及び/又はエンザルタミドでの事前治療は許容された。
本研究は、タキサン薬への感受性又は耐性を予測するために、基準点AR−V7状態の能力を評価する予測研究である。ドセタキセル又はカバジタキセルでの化学治療をまさに開始しようとしていた患者を登録し、基準点、臨床/生化学的応答の時点(仮に応答が発生したら)、ならびに臨床/放射線学的進行の時点での、最大3時点までの末梢血液CTCサンプル採取を受けた。ドセタキセルは、3週間ごとに、静脈内へ75mg/m2の用量で投与し、カバジタキセルは、3週間ごとに、静脈内へ25mg/m2の用量で投与した(プレドニゾンの5mgを、日に2回、両方に与えた)。
先に記述した、商業的に入手可能な、Alere(商標)AdnaTest platform (Alere Inc,Waltham,MA)の修正版を使用して、CTC分析を行った11。簡単に説明すると、ProstateCancerSelectキットを使用して、CTCの単離及び濃縮を実施し、ならびにCTCの有無を確かめるために、多重化逆転写ポリメラーゼ連鎖反応(qRT−PCR)のプライマーを伴う、ProstateCancerDetectキットを使用して、mRNA発現解析を行った(このプラットフォームは、CTC列挙型とは、互換性ではない)。次いで、前述のように、そのmRNAレベルでの完全長AR(AR−FL)及びAR−V7を検出するために、カスタムプライマーを使用した11。AR−FL転写に対するAR−V7転写の比率を計算して、AR−V7の相対存在量を決定した。
第一終点は、PSA応答率であり、治療後の任意の時点で、基準点から≧50%のPSA減少に達した(及び≧3週間維持された)患者の割合である。第二終点には、PSA無増悪期間(PSA−PFS)及び臨床/放射線無増悪期間(PFS)を含む。全生存期間(OS)は、予備的な終点とした。PSA進行は、≧3週間後に確認が必要な(PCWG2基準)、底部から≧25%のPSA増加(及び≧2ng/mLまで)と定義した23。臨床/放射線学的進行は、症状進行(疾患関連症状の悪化、又は新規のがん関連合併症)、もしくは放射線学的進行(CTスキャンで、軟部組織の標的病変の合計直径における≧20%拡大[RECIST基準24]、骨スキャンで、≧2の新規骨病変)、又は死亡の内、どれかが最初に発生した時点と定義した23。OSは、任意の原因によって死亡した時と定義した。
サンプルサイズは、PSA応答の第一終点に基づいて決定し、基準点でAR−V7陽性であった男性の30%であると考えられた。これまでの研究において11、エンザルタミド/アビラテロンで治療された患者は、AR−V7陽性及びAR−V7陰性患者の61%(95%CI、43%〜80%)において、PSA応答率に差異を示した。AR−V7状態の影響度は、エンザルタミド/アビラテロンで治療された患者に比べて、タキサンで治療された患者の文脈においては、より少ないと仮定されたので、PSA応答率での更に少ない差異を使用し、そのためその差異に対して95%CIの上限値が、<61%であった(これまでの研究から推定した点)。したがって、36人の患者のサンプルサイズは、観察される絶対差異が、30%の場合(AR−V7陰性の男性における45%PSA応答率及びAR−V7陽性の男性における15%PSA応答率)、60%上限値を有するAR−V7陽性及びAR−V7陰性患者の間のPSA応答率における差異に対して、両側で95%CIを持っていた。
患者特性
37人のCTC陽性患者を登録した。30人は、ドセタキセルの投与を受け、7人はカバジタキセルの投与を受けていた。検出可能なCTCを持つ37人の男性を特定するために、43人の患者を選別した(産出率86%、CTC陰性患者は、さらなる解析から除外した)。データ締切日(2014年、9月1日)で、全てのタキサンで治療された患者のフォローアップ期間の中央値は、7.7ヶ月(範囲、0.7〜19.0)であった。男性の45.9%(17/37)は、彼らの基準点CTCサンプルに、検出可能なAR−V7のmRNAを有していた。これらの患者において、AR−V7/AR−FL比率の中央値は、22.9%(範囲、2.6〜69.2%)であった(図14)。
表11.タキサンで治療された37患者の基本的特徴
*P値は、カテゴリー及び連続の各々の変数に対しての、フィッシャーの正確確率検定及びマン・ホイットニーのU検定に基づいている。
表12.タキサンで治療された37患者及びエンザルタミド/アビラテロンで治療された62患者の基本的特徴の比較
*P値は、カテゴリー及び連続の各々の変数に対しての、フィッシャーの正確確率検定及びマン・ホイットニーのU検定に基づいている。
PSA応答
タキサン治療でPSA応答に達した患者の全割合は、54%(20/37人、95%CI、37〜71%)であり、AR−V7状態による有意差は無かった。AR−V7陽性患者における、PSA応答率は、41%(7/17人、95%CI、18〜67%)であり、AR−V7陰性患者においては、65%(13/20人、95%CI、41〜85%)であり、24%の非有意差(P=0.194、その差異に対して95%CI、−13〜60%)であった。AR−V7状態による最高PSA応答を、図15に描写する。多変量ロジスティック回帰モデルにおいて、AR−FL発現及びエンザルタミド/アビラテロンの事前使用に対する調製後、AR−V7状態は、PSA応答に対して非予測的なままであった(OR 0.39、95%CI 0.06〜2.32、P=0.307)。
PSA無増悪期間(PSA−PFS)は、AR−V7状態によって著しく異なってはいなかった。PSA−PFSの中央値は、AR−V7陽性の男性で4.5ヶ月、及びAR−V7陰性の男性で6.2ヶ月(HR2.1、95%CI 0.9〜4.9、P=0.064)であった(図16A、実線)。AR−FL発現及びエンザルタミド/アビラテロンの事前使用に対して調整した、多変量コックスモデルにおいて、AR−V7状態は、PSA−PFSを予測する能力に非有意性を残しており(HR1.7、95%CI 0.6〜5.0、P=0.324)、AR−FLレベル(HR1.0、95%CI 0.9〜1.2)及びエンザルタミド/アビラテロンの事前使用(HR1.4、95%CI 0.4〜4.2)は、この多変量解析においても、PSA−PFSに非予測的であった。
臨床/放射線無増悪期間(PFS)は、AR−V7状態によって著しく異なってはいなかった。PFSの中央値は、AR−V7陽性の男性で5.1ヶ月、及びAR−V7陰性の男性で6.9ヶ月(HR2.8、95%CI 1.2〜6.9、P=0.017)であった(図16B、実線)。この差異は、有意に思えたが、AR−FL発現及びエンザルタミド/アビラテロンの事前使用に対して調整した、多変量コックスモデルにおいて、AR−V7状態は、PFSを予測する能力を欠いており(HR2.7、95%CI 0.8〜8.8、P=0.110)、AR−FLレベル(HR1.0、95%CI 0.9〜1.1)及びエンザルタミド/アビラテロンの事前使用(HR1.7、95%CI 0.5〜6.2)もまた、PFSに非予測的であった。
全生存期間(OS)もまた、AR−V7状態によって著しく異なってはいなかった。OSの中央値は、AR−V7陽性の男性で9.2ヶ月、及びAR−V7陰性の男性で14.7ヶ月(HR2.5、95%CI 0.8〜8.1、P=0.113)であった(図16C、実線)。AR−FL発現に対して調整した、多変量コックスモデルにおいて、AR−V7状態は、OSを予測する能力に非有意性を残しており(HR0.7、95%CI 0.1〜3.8、P=0.657)、AR−FLレベルもまた、OSに非予測的であった(HR1.3、95%CI 0.9〜1.8)。
PSA応答
未調整線形モデルにおいて、AR−V7状態と治療タイプの間に、著しい相互作用が観察された(P=0.002)。AR−FLレベル、化学療法の事前使用、及びエンザルタミド/アビラテロンの事前使用から成る調整モデルにおいても、その相互作用は、著しいままであった(P=0.006)。
未調整コックスモデルにおいて、AR−V7状態と治療タイプの間に、著しい相互作用が観察された(P<0.001)(図16A)。AR−FLレベル、化学療法の事前使用、及びエンザルタミド/アビラテロンの事前使用から成る調整モデルにおいても、その相互作用は、著しいままであった(P=0.001)。
未調整コックスモデルにおいて、AR−V7状態と治療タイプの間に、著しい相互作用が観察された(P<0.001)(図16B)。その調整モデルにおいて、その相互作用は、著しいままであった(P=0.003)。
未調整のコックスモデル(P=0.176)(図16C)又はその調整モデル(P=0.157)のいずれにおいても、AR−V7状態と治療タイプの間に、著しい相互作用は観察されなかった。
AR−V7陽性患者
AR−V7陽性の男性においては、タキサンでの治療が、AR指向療法より優れていると思われた。PSA応答は、タキサン治療の患者で41%(7/17)及びエンザルタミド/アビラテロン治療の患者で0%(0/18)であった(P<0.001)。AR−FLレベル、事前の化学療法、及びエンザルタミド/アビラテロンの事前使用に対して調整した、多変量線形モデルにおいて、タキサンでの治療は、エンザルタミド/アビラテロンよりも優位性を残していた(P<0.001)。更に、PSA−PFSの中央値は、エンザルタミド/アビラテロン治療の男性に比べて、タキサン治療の男性の方がより長期であった(HR0.22、95%CI 0.09〜0.53、P<0.001)(図16A、#/##)。AR−FLレベル及びエンザルタミド/アビラテロンの事前使用に対して調整した、多変量コックスモデルにおいて、タキサン療法は、AR指向療法よりも優位性を残していた(HR0.19、95%CI 0.07〜0.52、P=0.001)。同様に、PFS中央値は、エンザルタミド/アビラテロン治療の男性に比べて、タキサン治療の方がより長期であった(HR0.26、95%CI 0.11〜0.59、P=0.001)(図16B、#/##)。AR−FLレベル及びエンザルタミド/アビラテロンの事前使用に対して調整した、多変量コックスモデルにおいて、タキサン療法は、優位性を残していた(HR0.21、95%CI 0.07〜0.59、P=0.003)。最終的に、OS(予備的)中央値は、エンザルタミド/アビラテロンで治療された患者に比べて、タキサン治療の方が、数字的に優れていた(HR0.83、95%CI 0.34〜2.00、P=0.764)(図16C、#/##)。AR−FLレベル及びエンザルタミド/アビラテロンの事前使用に対して調整した、多変量コックスモデルにおいて、タキサン療法で生存期間が良好になる傾向があった(HR0.28、95%CI 0.07〜1.00、P=0.059)。
AR−V7陰性の男性におけるいずれの臨床結果に関しても、タキサン治療とAR指向療法の間に有意差は無かった。PSA応答は、タキサン治療の患者で65%(13/20)及びエンザルタミド/アビラテロン治療の患者で64%(28/44)であった(P=0.604)。多変量線形モデルにおいて、AR−FLレベル、事前の化学療法、及びエンザルタミド/アビラテロンの事前使用に対して調整後、この差異は、有意ではなかった(P=0.361)。PSA−PFSの中央値は、多変量コックスモデルにおいて、AR−FLレベル及びエンザルタミド/アビラテロンの事前使用に対して調整後でさえ(HR1.09、95%CI 0.51〜2.31、P=0.828)、エンザルタミド/アビラテロン治療の患者に比べて、タキサン治療の患者の方が、有意差が無かった(HR1.61、95%CI 0.84〜3.06、P=0.149)(図16A、*/**)。同様に、PFS中央値は、多変量コックス解析において、AR−FL及びエンザルタミド/アビラテロンの事前使用に対して調整後でさえ(HR1.02、95%CI 0.46〜2.25、P=0.959)、エンザルタミド/アビラテロン治療の患者に比べて、タキサン治療の方が、有意差が無かった(HR1.68、95%CI 0.84〜3.33、P=0.142)(図16B、*/**)。最終的に、OS(予備的)中央値は、単変量(HR2.26、95%CI 0.78〜6.62、P=0.134)(図16C、*/**)又は多変量(HR1.55、95%CI 0.49〜4.95、P=0.459)解析のいずれにおいても、当該2つの治療群間で、有意差が無かった。
21人のタキサンで治療された患者について、AR−V7に対して評価可能な基準点及び進行の時点で採取したCTCサンプルを組み合わせた。初期にAR−V7が検出不可能な男性の間で(n=9)、1人の患者がその後、一連のタキサン治療中にAR−V7陽性に転換し、一方8人の患者が、進行時点でAR−V7陰性を残していた。反対に、基準点で検出可能なAR−V7を持つ男性の間で(n=12)、7人の患者(58%)が、タキサン治療中にAR−V7陰性に転換し、一方5人の患者(42%)が、進行時点でAR−V7陽性を残していた。AR−V7状態における、これら転換の臨床的意義は、現在も不明である。
転移性CRPCの男性に対して、複数の利用可能な療法が存在する一方で、これらの患者に最適な治療を導くための分子バイオマーカーは、現在も無い。我々は、低いPSA応答、より短いPFS、及びより短いOSによって明らかになったように、AR−V7の検出が、アビラテロン及びエンザルタミドへの初期耐性に関連していることを、これまでに示してきた11。ここで、我々は、検出可能なAR−V7を持つ男性が、タキサンの化学療法に感受性を保持しており、そのAR−V7の影響は、化学療法によるよりも、AR指向療法の文脈において、より著しく、タキサンは、AR−V7陽性の男性において(しかしAR−V7陰性の男性にではなく)、エンザルタミド/アビラテロンよりも、優れた効能を有している可能性がある、ことを示している。現在の研究は、タキサン化学療法を受けている患者における、AR−V7の最初の予測分析を示し、我々のデータの総和は、AR−V7が、CRPCにおける治療選択マーカーになる可能性があることを示唆している。
Claims (25)
- 前立腺がん患者からのサンプルにおいて、完全長アンドロゲン受容体(「AR−FL」)及びアンドロゲン受容体変異体7(「AR−V7」)転写産物の両方を増幅することにより、AR−V7のレベルを決定することを含む方法であって、前記サンプルが、循環性腫瘍細胞について濃縮されていることを特徴する方法。
- 前記増幅が、ポリメラーゼ連鎖反応(「PCR」)を使用して行われる、請求項1に記載の方法。
- 前記PCRが、多重化PCRであるか又はそれを含む、請求項2に記載の方法。
- 前記PCRが、定量的逆転写ポリメラーゼ連鎖反応(「qRT−PCR」)であるか又はそれを含む、請求項2に記載の方法。
- 前記PCRが、配列が、
(1)AR−V7(順方向)5′−CCATCTTGTCGTCTTCGGAAATGTTA−3′ SEQ ID番号:3、及びAR−V7(逆方向)5′−TTGAATGAGGCAAGTCAGCCTTTCT−3′ SEQ ID番号:4、及び/又は
(2)AR−FL(順方向)5′−CAGCCTATTGCGAGAGAGCTG−3′ SEQ ID番号:1、及びAR−FL(逆方向)5′−GAAAGGATCTTGGGCACTTGC−3′ SEQ ID番号:2
であるプライマーであるか又はそれらの配列を含むプライマーを利用する、請求項2に記載の方法。 - 前記PCRが、ヌクレオチド類似体を含む、1つ以上のプライマーを利用する、請求項2に記載の方法。
- 前記PCRが、ヌクレオチド置換を含む、1つ以上のプライマーを利用する、請求項2に記載の方法。
- 前記患者が、去勢抵抗性前立腺がんの患者(「CRPC」)である、請求項1に記載の方法。
- 前記患者が、ARシグナル伝達阻害剤で治療されている又は治療されたことがある、請求項8に記載の方法。
- 前記患者が、CYP17阻害剤で治療されている又は治療されたことがある、請求項8に記載の方法。
- 前記患者が、アビラテロン、エンザルタミド、及びそれらの組み合わせから成る群から選択される薬剤での治療を開始しているCRPC患者である、請求項8に記載の方法。
- 前記患者が、アビラテロン、エンザルタミド、及びそれらの組み合わせから成る群から選択される薬剤に耐性のCRPC患者である、請求項8に記載の方法。
- 複数サンプルに基づく決定を繰り返す工程を更に含み、各サンプルが、前立腺がんの診断後の異なる時点で取得される、請求項1に記載の方法。
- 複数の前記時点が、一連の治療中に発生する、請求項13に記載の方法。
- 少なくとも1つの時点が、基準の時点である、請求項13に記載の方法。
- 少なくとも1つの時点が、臨床又は生化学的応答の瞬間である、請求項13に記載の方法。
- 前記臨床又は生化学的応答が、前立腺特異性抗原の測定であるか又はそれを含む、請求項16に記載の方法。
- 少なくとも1つの時点が、臨床又は放射線学的進行の瞬間である、請求項13に記載の方法。
- 前記臨床又は放射線学的進行が、疾患関連症状の悪化、がん関連合併症、放射線学的進行、軟部組織の標的病変の合計直径の拡大、骨病変の数の増加、死亡、及びそれらの組み合わせから成る群から選択された、症状の進行をモニターすることを含む、請求項18に記載の方法。
- 前記決定工程が、ハイブリダイゼーションアッセイの活用を含む、請求項1に記載の方法。
- 前記ハイブリダイゼーションアッセイが、新鮮な又は解剖した腫瘍サンプルの現場でのハイブリダイゼーションである、請求項20に記載の方法。
- 前記決定工程が、AR−FLの量と比較したAR−V7の量を決定するためのPCRを含む、請求項1に記載の方法。
- 前記前立腺がん患者が、一連の治療を受けており、前記決定工程が、その一連の治療にわたり、複数の時点で繰り返される、請求項1に記載の方法。
- 前記AR−V7が、最初の決定工程において、初期に検出不可能であり、その一連の治療にわたり、経過後の時点で実施された、少なくとも1回の後続決定工程において、AR−FLに対するAR−V7の絶対複製数の比率が、1以上である、請求項23に記載の方法。
- 各決定工程が、AR−FLに対するAR−V7の絶対複製数の比率を決定することを含む、請求項23に記載の方法。
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