JP7324144B2 - 癌処置様式 - Google Patents
癌処置様式 Download PDFInfo
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- JP7324144B2 JP7324144B2 JP2019541403A JP2019541403A JP7324144B2 JP 7324144 B2 JP7324144 B2 JP 7324144B2 JP 2019541403 A JP2019541403 A JP 2019541403A JP 2019541403 A JP2019541403 A JP 2019541403A JP 7324144 B2 JP7324144 B2 JP 7324144B2
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- lung cancer
- smarca2
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- cancer
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Description
本出願は、2017年2月2日に出願された米国仮特許出願第62/453,929号及び2017年3月31日に出願された米国仮特許出願第62/479,878号の利益を主張する。上述の各出願の全内容は、その全体の参照により本明細書に組み込まれる。
本出願は、EFS-Webを介してASCII形式で提出された配列表を含み、その全体の参照により本明細書に組み込まれる。2018年1月17日に作成された前記ASCIIコピーは、EPIZ-074001WO_ST25.txtという名称であり、そのサイズは196,906バイトである。
特許又は出願ファイルは、カラーで作成された少なくとも1つの図面を含む。カラー図面を含むこの特許又は特許出願公開のコピーは、請求及び必要な料金の支払いに応じて特許庁によって提供されるであろう。
本開示のいくつかの態様は、EZH2阻害剤による、EZH2(zeste2ポリコーム抑制複合体2のエンハンサー)機能に依存する細胞増殖性障害、例えば癌の処置に関して有用な処置様式、例えば方法、戦略、組成物、組み合わせ、及び剤形を提供する。本開示のいくつかの態様は、細胞増殖性障害の状態のサブタイプ、例えば特定の癌のサブタイプがEZH2機能に依存し、したがってEZH2阻害剤で効果的に処置できるという認識に基づいている。いくつかの実施形態では、EZH2依存性サブタイプは、幹細胞、幹様細胞、前駆細胞、又は未成熟細胞に由来する過剰増殖性細胞又は細胞集団、例えば、癌細胞又は癌細胞集団の存在によって特徴付けられ、少なくとも1つの過剰増殖性細胞又は細胞集団、例えば少なくとも1つの癌細胞は、癌細胞をEZH2機能に依存させる遺伝子病変及び/又はエピジェネティック病変を含む。いくつかの実施形態では、遺伝子病変又はエピジェネティック病変は、1つ以上のSWI/SNF複合体メンバー、例えば、INI-1(SMARCB1、SWI/SNF関連、マトリックス関連、アクチン依存性クロマチン調節因子、サブファミリーb、メンバー1としても知られる)、SMARCA2(SWI/SNF関連、マトリックス関連、アクチン依存性クロマチン調節因子、サブファミリーa、メンバー2;時にはBRM、SNF2L2、又はSNF2LAとも呼ばれる)、及び/又はSMARCA4(SWI/SNF関連、マトリックス関連、アクチン依存性クロマチン調節因子、サブファミリーa、メンバー4;時にはブラフマーホモログ、BRG1、CSS4、MRD16、RTPS2、SNF2L4、又はSNF2LBとも呼ばれる)機能の喪失をもたらす。例えば、いくつかの実施形態では、細胞増殖性障害は、SMARCA2及び/又はSMARCA4の機能の喪失をもたらす遺伝子病変又はエピジェネティック病変によって特徴付けられる。
又はその薬学的に許容される塩を有し;式中、
R701は、H、F、OR707、NHR707、-(C≡C)-(CH2)n7-R708、フェニル、5員又は6員ヘテロアリール、C3~8シクロアルキル、又は1~3個のヘテロ原子を含む4~7員ヘテロシクロアルキルであり、フェニル、5員又は6員ヘテロアリール、C3~8シクロアルキル又は4~7員ヘテロシクロアルキルはそれぞれ独立に、ハロ、C1~3アルキル、OH、O-C1~6アルキル、NH-C1~6アルキル、及び1~3個のヘテロ原子を含むC3~8シクロアルキル又は4~7員ヘテロシクロアルキルで置換されたC1~3アルキルから選択される1つ以上の基で任意選択により置換され、ここで、O-C1~6アルキル及びNH-C1~6アルキルのそれぞれは、ヒドロキシル、O-C1~3アルキル、又はNH-C1~3アルキルで任意選択により置換され、O-C1~3アルキル及びNH-C1~3アルキルのそれぞれは、任意選択によりO-C1~3アルキル又はNH-C1~3アルキルでさらに置換され;
R702及びR703のそれぞれは独立に、H、ハロ、C1~4アルキル、C1~6アルコキシル、又はC6~C10アリールオキシであり、それぞれは、1つ以上のハロで任意選択により置換され;
R704及びR705のそれぞれは独立に、C1~4アルキルであり;
R706は、N(C1~4アルキル)2で置換されたシクロヘキシルであり、ここで、C1~4アルキルの一方又は両方は、C1~6アルコキシで任意選択により置換される;又はR706はテトラヒドロピラニルであり;
R707は、ヒドロキシル、C1~4アルコキシ、アミノ、モノ-又はジ-C1~4アルキルアミノ、C3~8シクロアルキル、及び1~3ヘテロ原子を含む4~7員ヘテロシクロアルキルから選択される1つ以上の基で任意選択により置換されたC1~4アルキルであり、ここで、C3~8シクロアルキル又は4~7員ヘテロシクロアルキルはそれぞれ独立に、任意選択によりC1~3アルキルでさらに置換され;
R708は、OH、ハロ、及びC1~4アルコキシから選択される1つ以上の基で任意選択により置換されたC1~4アルキル、1~3個のヘテロ原子を含む4~7員ヘテロシクロアルキル、又はO-C1~6アルキルであり、ここで、4~7員ヘテロシクロアルキルは、任意選択によりOH又はC1~6アルキルでさらに置換されてもよく;そして
n7は0、1、又は2である。
又はその薬学的に許容される塩を有することができる。
この式において:
R801はC1~6アルキル、C2~6アルケニル、C2~6アルキニル、C3~8シクロアルキル、1~3個のヘテロ原子を含む4~7員ヘテロシクロアルキル、フェニル又は5員又は6員ヘテロアリールであり、その各々がO-C1~6アルキル-Rx又はNH-C1~6アルキル-Rxで置換されており、ここで、Rxはヒドロキシル、O-C1~3アルキル又はNH-C1~3アルキルであり、Rxは、これがヒドロキシルである場合を除いて、O-C1~3アルキル又はNH-C1~3アルキルで任意選択的にさらに置換されており;あるいはR801は-Q2-T2で置換されたフェニルであり、ここで、Q2は結合又はハロ、シアノ、ヒドロキシル若しくはC1~C6アルコキシで任意選択的に置換されたC1~C3アルキルリンカーであり、T2は4員~12員ヘテロシクロアルキルで任意選択的に置換されており;及びR801は任意選択的にさらに置換されており;
R802及びR803は各々独立にH、ハロ、C1~4アルキル、C1~6アルコキシル又はC6~C10アリールオキシであり、各々が1つ又は複数のハロで任意選択的に置換されており;
R804及びR805は各々独立にC1~4アルキルであり;並びに
R806は-Qx-Txであり、ここで、Qxは結合又はC1~4アルキルリンカーであり、TxはH、任意選択的に置換されたC1~4アルキル、任意選択的に置換されたC3~C8シクロアルキル又は任意選択的に置換された4員~14員ヘテロシクロアルキルである。
又はその薬学的に許容される塩若しくはエステルを有することができる。
この式において:
R2、R4及びR12は各々独立にC1~6アルキルであり;
R6はC6~C10アリール又は5員若しくは6員ヘテロアリールであり、その各々が1つ又は複数の-Q2-T2で任意選択的に置換されており、ここで、Q2は結合、又はハロ、シアノ、ヒドロキシル若しくはC1~C6アルコキシで任意選択的に置換されたC1~C3アルキルリンカーであり、T2はH、ハロ、シアノ、-ORa、-NRaRb、-(NRaRbRc)+A-、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRbC(O)Ra、-NRbC(O)ORa、-S(O)2Ra、-S(O)2NRaRb又はRS2であり、ここで、Ra、Rb及びRcは各々独立にH又はRS3であり、A-は薬学的に許容されるアニオンであり、RS2及びRS3は各々独立にC1~C6アルキル、C3~C8シクロアルキル、C6~C10アリール、4~12員ヘテロシクロアルキル又は5員若しくは6員ヘテロアリールであり、あるいはRa及びRbは、それらが結合しているN原子と一緒に0又は1個の追加のヘテロ原子を有する4~12員ヘテロシクロアルキル環を形成し、RS2と、RS3と、Ra及びRbで形成される4~12員ヘテロシクロアルキル環との各々は、1つ又は複数の-Q3-T3で任意選択的に置換されており、ここで、Q3は結合、又はハロ、シアノ、ヒドロキシル又はC1~C6アルコキシで各々任意選択的に置換されたC1~C3アルキルリンカーであり、T3はハロ、シアノ、C1~C6アルキル、C3~C8シクロアルキル、C6~C10アリール、4~12員ヘテロシクロアルキル、5員又は6員ヘテロアリール、ORd、COORd、-S(O)2Rd、-NRdRe及びC(O)NRdReからなる群から選択され、Rd及びReは各々独立にH又はC1~C6アルキルであるか、又はQ3-T3はオキソであり;あるいは任意の2つの隣接する-Q2-T2は、それらが結合している原子と一緒に5員又は6員環を形成し、当該5員又は6員環は、N、O及びSから選択される1~4個のヘテロ原子を任意選択的に含み、ハロ、ヒドロキシル、COOH、C(O)O-C1~C6アルキル、シアノ、C1~C6アルコキシル、アミノ、モノ-C1~C6アルキルアミノ、ジ-C1~C6アルキルアミノ、C3~C8シクロアルキル、C6~C10アリール、4~12員ヘテロシクロアルキル及び5員又は6員ヘテロアリールからなる群から選択される1つ又は複数の置換基で任意選択的に置換されており;
R7は-Q4-T4であり、ここで、Q4は結合、C1~C4アルキルリンカー又はC2~C4アルケニルリンカーであり、各リンカーはハロ、シアノ、ヒドロキシル又はC1~C6アルコキシで任意選択的に置換されており、T4はH、ハロ、シアノ、NRfRg、-ORf、-C(O)Rf、-C(O)ORf、-C(O)NRfRg、-C(O)NRfORg、-NRfC(O)Rg、-S(O)2Rf又はRS4であり、ここで、Rf及びRgは各々独立にH又はRS5であり、RS4及びRS5は各々独立にC1~C6アルキル、C2~C6アルケニル、C2~C6アルキニル、C3~C8シクロアルキル、C6~C10アリール、4~12員ヘテロシクロアルキル又は5員若しくは6員ヘテロアリールであり、RS4及びRS5は各々1つ又は複数の-Q5-T5で任意選択的に置換されており、ここで、Q5は結合、C(O)、C(O)NRk、NRkC(O)、S(O)2又はC1~C3アルキルリンカーであり、RkはH又はC1~C6アルキルであり、T5はH、ハロ、C1~C6アルキル、ヒドロキシル、シアノ、C1~C6アルコキシル、アミノ、モノ-C1~C6アルキルアミノ、ジ-C1~C6アルキルアミノ、C3~C8シクロアルキル、C6~C10アリール、4~12員ヘテロシクロアルキル、5員若しくは6員ヘテロアリール又はS(O)qRqであり、ここで、qは0、1又は2であり、RqはC1~C6アルキル、C2~C6アルケニル、C2~C6アルキニル、C3~C8シクロアルキル、C6~C10アリール、4~12員ヘテロシクロアルキル又は5員若しくは6員ヘテロアリールであり、T5は、これがH、ハロ、ヒドロキシル又はシアノである場合を除いて、ハロ、C1~C6アルキル、ヒドロキシル、シアノ、C1~C6アルコキシル、アミノ、モノ-C1~C6アルキルアミノ、ジ-C1~C6アルキルアミノ、C3~C8シクロアルキル、C6~C10アリール、4~12員ヘテロシクロアルキル及び5員又は6員ヘテロアリールからなる群から選択される1つ又は複数の置換基で任意選択的に置換されており;あるいは-Q5-T5はオキソであり;並びに
R8はH、ハロ、ヒドロキシル、COOH、シアノ、RS6、ORS6又はCOORS6であり、ここで、RS6はC1~C6アルキル、C2~C6アルケニル、C2~C6アルキニル、C3~C8シクロアルキル、4~12員ヘテロシクロアルキル、アミノ、モノ-C1~C6アルキルアミノ又はジ-C1~C6アルキルアミノであり、RS6はハロ、ヒドロキシル、COOH、C(O)O-C1~C6アルキル、シアノ、C1~C6アルコキシル、アミノ、モノ-C1~C6アルキルアミノ及びジ-C1~C6アルキルアミノからなる群から選択される1つ又は複数の置換基で任意選択的に置換されており;あるいはR7及びR8は、それらが結合しているN原子と一緒に、0~2個の追加のヘテロ原子を有する4~11員ヘテロシクロアルキル環を形成し、R7及びR8で形成された4~11員ヘテロシクロアルキル環は1つ又は複数の-Q6-T6で任意選択的に置換されており、ここで、Q6は結合、C(O)、C(O)NRm、NRmC(O)、S(O)2又はC1~C3アルキルリンカーであり、RmはH又はC1~C6アルキルであり、T6はH、ハロ、C1~C6アルキル、ヒドロキシル、シアノ、C1~C6アルコキシル、アミノ、モノ-C1~C6アルキルアミノ、ジ-C1~C6アルキルアミノ、C3~C8シクロアルキル、C6~C10アリール、4~12員ヘテロシクロアルキル、5員若しくは6員ヘテロアリール又はS(O)pRpであり、ここで、pは0、1又は2であり、RpはC1~C6アルキル、C2~C6アルケニル、C2~C6アルキニル、C3~C8シクロアルキル、C6~C10アリール、4~12員ヘテロシクロアルキル又は5員若しくは6員ヘテロアリールであり、T6は、これがH、ハロ、ヒドロキシル又はシアノである場合を除いて、ハロ、C1~C6アルキル、ヒドロキシル、シアノ、C1~C6アルコキシル、アミノ、モノ-C1~C6アルキルアミノ、ジ-C1~C6アルキルアミノ、C3~C8シクロアルキル、C6~C10アリール、4~12員ヘテロシクロアルキル及び5員又は6員ヘテロアリールからなる群から選択される1つ又は複数の置換基で任意選択的に置換されており;あるいは-Q6-T6はオキソである。
又はその薬学的に許容される塩であり、式中、Q2は、結合リンカー又はメチルリンカーであり、T2は、H、ハロ、-ORa、-NRaRb、-(NRaRbRc)+A-、又はS(O)2NRaRbであり、R7は、ピペリジニル、テトラヒドロピラン、シクロペンチル、又はシクロヘキシルであり、それぞれは、任意選択的に1つの-Q5-T5で置換され、R8はエチルである。
又はその薬学的に許容される塩である。化合物44は、タゼメトスタット、EPZ006438、又は6438とも呼ばれる。
を有するGSK-126、その立体異性体、その薬学的に許容される塩又は溶媒和物を含む、これらから本質的になる、又はこれらからなり得る。本明細書で提供される戦略、処置様式、方法、組み合わせ、及び組成物のいくつかの実施形態では、EZH2阻害剤は、それぞれ参照によりその全開示内容が本明細書に組み入れられる米国特許第8,536,179号明細書(いくつかある化合物の中でも特にGSK-126を記載し、国際公開第2011/140324号パンフレットに対応する)に記載されているEZH2阻害剤である。
の化合物又はその薬学的に許容される塩である(例えば、その内容が本明細書に組み入れられる米国特許出願公開第2015/0368229号明細書を参照)。
又はその薬学的に許容される塩と、1つ又は複数の治療剤とを、薬学的に好適なキャリア又は賦形剤と混合して、本明細書に記載の疾患又は状態を処置又は予防するための用量で含む医薬組成物も提供する。本開示の医薬組成物はまた、他の治療剤又は治療法と併用して、同時に、逐次的に又は交互に投与することもできる。
SWI/SNF複合体タンパク質の状態は、様々な肺癌細胞株で決定された。試験したすべての肺癌細胞株の約1/3が、SWI/SNFメンバータンパク質の異常を示した。以下の表2Aは、1つ以上のSWI-SNF変化を有すると特定された31個の肺癌細胞株におけるSMARCA2及びSMARCA4タンパク質の状態を示している。濃い灰色は機能の喪失を示し、薄い灰色は正常な機能を示す。表2Aに示すように、31個のSWI/SNF機能喪失肺癌細胞株のうち10個は、SMARCA4の単一喪失を示し、表の上部に列挙された31株のうち8株は、SMARCA2/SMARCA4の二重喪失を示した。
SMARCA4単一喪失NSCLC細胞株及びSMARCA2/SMARCA4二重喪失NSCLC細胞株の両方を、NSCLC異種移植片モデルに関して臨床的に達成可能な用量(約250mg/kg体重)で、インビボでEZH2阻害剤タゼメトスタットを用いて処理した(図3及び図4)。インビトロデータと一致して、腫瘍成長の阻害は、SMARCA4単一喪失異種移植片よりもSMARCA2/SMARCA4二重喪失異種移植片でより顕著であった。4つのSMARCA2/SMARCA4二重喪失細胞株のうち2つでは、腫瘍の退縮が観察された(図3)。
本明細書で提供されるデータは、肺癌のサブタイプであるSMARCA2/SMARCA4二重喪失NSCLCが、EZH2阻害により効果的に処置できることを実証している。SMARCA2/SMARCA4二重喪失を示すものを含む原発性NSCLC腫瘍は、典型的には、低分化腺癌タイプ(例えば、固形腺癌)であり、上皮間葉転換(EMT)の特徴(例えば、低いE-カドヘリン発現レベル及び高いビメンチン発現レベル)を頻繁に示す。これらの特徴は、ラブドイド腫瘍の特徴(例えば、低分化及び間葉様)と一致し、したがって、SMARCA2/SMARCA4二重喪失によって特徴付けられるNSCLCの以前は認識されていなかったラブドイド様サブタイプを示している。SMARCA2とSMARCA4の二重喪失は、NSCLC患者の生存率の低下と相関する(例えば、参照により本明細書に組み込まれる、Reisman et al. Cancer Res 2003を参照)。さらに、二重喪失腫瘍は、NSCLCに関連する他の変異(例えば、EGFR、KRAS、ALK融合)について陰性である頻度が高く、したがって療法に利用可能な選択肢が制限される。したがって、SMARCA2/SMARCA4二重喪失NSCLC腫瘍クラスは、まだ対処されていない医学的要求の高い肺癌のサブタイプを表す。本開示は、EZH2阻害が腫瘍成長の阻害及び/又はそのような腫瘍における望ましい臨床結果の誘発に有効であることを実証する。
SMARCA2
>NM_001289396.1ホモサピエンスSWI/SNF関連、マトリックス関連、アクチン依存性クロマチン調節因子、サブファミリーa、メンバー2(SMARCA2)、転写変異体3、mRNA
>NM_001128849.1ホモサピエンスSWI/SNF関連、マトリックス関連、アクチン依存性クロマチン調節因子、サブファミリーa、メンバー4(SMARCA4)、転写変異体1、mRNA
本明細書、例えば、背景、要約、詳細な説明、実施例、及び/又は参考文献のセクションで言及されたすべての刊行物、特許、特許出願、特許公報、及びデータベースエントリ(例えば、配列データベースエントリ)は、個々の出版物、特許、特許出願、特許公報、及びデータベースエントリが参照により具体的かつ個別に本明細書に組み込まれるかのように、参照によりそれらの全内容が本明細書に組み込まれる。矛盾する場合は、本明細書のあらゆる定義を含む本出願が優先される。
特段の記載がない限り、本明細書で使用されるすべての科学技術用語は、本開示が属する分野の当業者によって一般的に理解される意味と同じ意味を有する。本明細書では、単数形は、そうでないと明確に文脈に示されない限り複数形も含む。本明細書で言及されるすべての出版物、特許出願、特許、及びその他の参考文献は、参照により組み込まれる。本明細書で引用される参考文献は、特許請求された発明の先行技術であると認められない。矛盾する場合は、定義を含む本明細書が優先される。さらに、材料、方法、及び例は、単に例示目的であり、限定することを意図したものではない。
本発明は、例えば、以下の項目を提供する。
(項目1)
SMARCA2及び/又はSMARCA4の機能の喪失を示す細胞又は細胞集団によって特徴付けられる細胞増殖性障害を有するか、又はそれと診断された対象にzesteホモログ2(EZH2)阻害剤のエンハンサーを投与することを含む方法。
(項目2)
それを必要とする対象の細胞増殖性障害を処置する方法であって、治療有効量のzesteホモログ2(EZH2)阻害剤のエンハンサーを前記対象に投与することを含み、前記細胞増殖性障害が、SMARCA2及び/又はSMARCA4の機能の喪失を示す細胞又は細胞集団によって特徴付けられる、方法。
(項目3)
前記細胞増殖性障害が肺の細胞増殖性障害である、項目1又は2に記載の方法。
(項目4)
それを必要とする対象の肺の細胞増殖性障害を処置する方法であって、治療有効量のzesteホモログ2(EZH2)阻害剤のエンハンサーを前記対象に投与することを含む、方法。
(項目5)
前記細胞増殖性障害が、SMARCA2機能の喪失及び/又はSMARCA4機能の喪失を示す細胞又は細胞集団を含むか、又はそれらによって特徴付けられる、項目4に記載の方法。
(項目6)
前記細胞増殖性障害が、SMARCA2機能及びSMARCA4機能の喪失を示す細胞又は細胞集団を含むか、又はそれらによって特徴付けられる、項目1、2、又は4のいずれか一項に記載の方法。
(項目7)
前記細胞増殖性障害が、幹細胞由来、幹様細胞由来、又は前駆細胞由来によって特徴付けられる、項目1、2、又は4のいずれか一項に記載の方法。
(項目8)
前記肺の細胞増殖性障害が、肺の悪性腫瘍又は病変によって特徴付けられる、項目1、2、又は4のいずれか一項に記載の方法。
(項目9)
前記悪性腫瘍又は病変が原発巣である、項目8に記載の方法。
(項目10)
前記悪性腫瘍又は病変が、二次病変又は転移性病変であるか、又はそれらによって特徴付けられる、項目8に記載の方法。
(項目11)
前記悪性腫瘍が、悪性肺新生物、癌腫、又はカルチノイド腫瘍である、項目8に記載の方法。
(項目12)
前記肺の細胞増殖性障害が、アスベスト誘発過形成、扁平上皮化生、及び良性反応性中皮化生である、項目1、2、又は4のいずれか一項に記載の方法。
(項目13)
前記肺の細胞増殖性障害が肺癌である、項目1、2、又は4のいずれか一項に記載の方法。
(項目14)
前記肺癌が小細胞肺癌である、項目13に記載の方法。
(項目15)
前記肺癌が非小細胞肺癌である、項目13に記載の方法。
(項目16)
前記肺癌が扁平上皮癌である、項目13に記載の方法。
(項目17)
前記肺癌が腺癌である、項目13に記載の方法。
(項目18)
前記肺癌が小細胞癌である、項目13に記載の方法。
(項目19)
前記肺癌が大細胞癌である、項目13に記載の方法。
(項目20)
前記肺癌が腺扁平上皮癌である、項目13に記載の方法。
(項目21)
前記肺癌が中皮腫である、項目13に記載の方法。
(項目22)
前記細胞増殖性疾患が、原発性腫瘍によって特徴付けられ、前記原発性腫瘍が、
(A)SMARCA2/SMARCA4二重喪失を示し;かつ
(B)低分化型であり、かつ/又は上皮間葉転換(EMT)の特徴を示す、項目1、2、又は4のいずれか一項に記載の方法。
(項目23)
前記原発性腫瘍が、低いE-カドヘリン発現レベル及び高いビメンチン発現レベルを示す、項目22に記載の方法。
(項目24)
前記対象が、前記EZH2阻害剤の投与と同時に又は時間的に近接して追加の治療薬が既に投与された、又は投与されている、項目1、2、又は4のいずれか一項に記載の方法。
(項目25)
前記追加の治療薬が標準治療剤である、項目24に記載の方法。
(項目26)
前記追加の治療薬が、図式1に記載の薬剤であるか、若しくはそれを含む、又は図式1に記載の2つ以上の薬剤の組み合わせであるか、若しくはそれを含む、項目25に記載の方法。
(項目27)
前記追加の治療薬が免疫チェックポイント阻害剤である、項目24に記載の方法。
(項目28)
前記免疫チェックポイント阻害剤が、CTLA4阻害剤、PD-1阻害剤及び/若しくはPD-LI阻害剤、LAG3阻害剤、B7-H3阻害剤、又はTim3阻害剤である、項目27に記載の方法。
(項目29)
前記免疫チェックポイント阻害剤が、イピリムマブ、チシリムマブ、AGEN-1884、ニボルマブ、ペンブロリズマブ、アテゾリズマブ、デュルバルマブ、アベルマブ、BMS-936559、AMP-224、MEDI-0680、TSR-042、BGB-108、STI-1014、KY-1003、ALN-PDL、BGB-A317、KD-033、REGN-2810、PDR-001、SHR-1210、MGD-013、PF-06801591、CX-072、IMP-731、LAG-525、BMS-986016、GSK-2831781、エノブリツズマブ、1241-8H9、DS-5573、MBG-453、又はそれらの組み合わせを含む、項目28に記載の方法。
(項目30)
前記EZH2阻害剤及び前記追加の治療薬が前記対象に連続的に投与される、項目24に記載の方法。
(項目31)
前記EZH2阻害剤及び前記追加の治療薬が、異なる投与経路を介して異なる間隔で投与される、項目24に記載の方法。
(項目32)
前記EZH2阻害剤が1日に2回経口投与される、項目1、2、又は4のいずれか一項に記載の方法。
(項目33)
SMARCA2及び/又はSMARCA4タンパク質の発現及び/又はSMARCA2及び/又はSMARCA4タンパク質の機能を検出することをさらに含む、項目1、2、又は4のいずれか一項に記載の方法。
(項目34)
SMARCA2及び/又はSMARCA4タンパク質の発現及び/又は機能が:
(a)前記対象から生体試料を得ること;
(b)前記生体試料又はその一部を、SMARCA2又はSMARCA4に特異的に結合する抗体に接触させること;及び
(c)SMARCA2又はSMARCA4に結合した抗体の量を検出することを含む方法によって評価される、項目33に記載の方法。
(項目35)
前記対象から得られた生体試料におけるSMARCA2タンパク質をコードする遺伝子及び/又はSMARCA4タンパク質をコードする遺伝子のゲノム変異を検出することをさらに含む、項目1、2、又は4のいずれか一項に記載の方法。
(項目36)
前記ゲノム変異が:
(a)前記対象から生体試料を得ること;
(b)前記生体試料におけるSMARCA2タンパク質又はその一部をコードする少なくとも1つのDNA配列、及び/又はSMARCA4タンパク質又はその一部をコードする少なくとも1つのDNA配列を配列決定すること;及び
(c)SMARCA2タンパク質又はその一部をコードする前記少なくとも1つのDNA配列、及び/又はSMARCA4タンパク質又はその一部をコードする前記少なくとも1つのDNA配列が、前記SMARCA2タンパク質又は前記SMARCA4タンパク質の発現及び/又は機能に影響を及ぼす変異を含むかどうかを決定すること
を含む方法によって検出される、項目35に記載の方法。
(項目37)
前記EZH2阻害剤が、ヒストン3のリシン27(H3K27)のトリメチル化を阻害する、項目1又は2に記載の方法。
(項目38)
対象から得られた試料におけるSMARCA2及び/又はSMARCA4の機能の喪失を検出することを含む方法。
(項目39)
前記対象が癌を有する、項目38に記載の方法。
(項目40)
SMARCA2及び/又はSMARCA4の機能の喪失が前記対象で検出された場合に、EZH2阻害剤を前記対象に投与することをさらに含む、項目38又は39に記載の方法。
(項目41)
前記SMARCA2機能の喪失が、SMARCA2タンパク質をコードする遺伝子のゲノム変異に関連せず、かつ/又はSMARCA4機能の喪失が、SMARCA4をコードする遺伝子のゲノム変異に関連する、項目40に記載の方法。
(項目42)
前記対象がNSCLCを有する、項目38に記載の方法。
(項目43)
前記EZH2阻害剤が、
(タゼメトスタット)、又はその薬学的に許容される塩である、項目1、2、又は4のいずれか一項に記載の方法。
(項目44)
前記EZH2阻害剤が、
、その立体異性体、薬学的に許容される塩、及び/又は溶媒和物である、項目1、2、又は4のいずれか一項に記載の方法。
(項目45)
前記EZH2阻害剤が、
又はその薬学的に許容される塩である、項目1、2、又は4のいずれか一項に記載の方法。
(項目46)
前記EZH2阻害剤が、
、その立体異性体、薬学的に許容される塩、及び/又は溶媒和物である、項目1、2、又は4のいずれか一項に記載の方法。
(項目47)
前記EZH2阻害剤が、
、その立体異性体、薬学的に許容される塩、及び/又は溶媒和物である、項目1、2、又は4のいずれか一項に記載の方法。
(項目48)
前記EZH2阻害剤が、
、その立体異性体、薬学的に許容される塩、及び/又は溶媒和物である、項目1、2、又は4のいずれか一項に記載の方法。
(項目49)
前記EZH2阻害剤が経口投与される、項目1、2、又は4のいずれか一項に記載の方法。
(項目50)
前記EZH2阻害剤が経口錠剤として製剤化される、項目1、2、又は4のいずれか一項に記載の方法。
(項目51)
前記EZH2阻害剤が、10mg/kg/日~1600mg/kg/日の用量で投与される、項目1、2、又は4のいずれか一項に記載の方法。
(項目52)
前記EZH2阻害剤が、約100mg、約200mg、約400mg、約800mg、又は約1600mgの用量で投与される、項目1、2、又は4のいずれか一項に記載の方法。
(項目53)
前記EZH2阻害剤が約800mgの用量で投与される、項目1、2、又は4のいずれか一項に記載の方法。
(項目54)
前記EZH2阻害剤が1日2回(BID)投与される、項目1、2、又は4のいずれか一項に記載の方法。
(項目55)
それを必要とする対象の細胞増殖性障害を処置するためのzesteホモログ2(EZH2)阻害剤のエンハンサーの使用であって、治療有効量のzesteホモログ2(EZH2)阻害剤のエンハンサーを前記対象に投与することを含み、前記細胞増殖性障害が、SMARCA2及び/又はSMARCA4の機能の喪失を示す細胞又は細胞集団によって特徴付けられる、使用。
(項目56)
前記細胞増殖性障害が肺の細胞増殖性障害である、項目55に記載の使用。
(項目57)
それを必要とする対象の肺の細胞増殖性障害を処置するための、zesteホモログ2(EZH2)阻害剤のエンハンサーの使用であって、治療有効量のzesteホモログ2(EZH2)阻害剤のエンハンサーを前記対象に投与することを含む、使用。
(項目58)
前記細胞増殖性障害が、SMARCA2機能の喪失及び/又はSMARCA4機能の喪失を示す細胞又は細胞集団を含むか、又はそれらによって特徴付けられる、項目57に記載の使用。
(項目59)
前記細胞増殖性障害が、SMARCA2機能及びSMARCA4機能の喪失を示す細胞又は細胞集団を含むか、又はそれらによって特徴付けられる、項目55~58のいずれか一項に記載の使用。
(項目60)
前記細胞増殖性障害が、幹細胞由来、幹様細胞由来、又は前駆細胞由来によって特徴付けられる、項目55~59のいずれか一項に記載の使用。
(項目61)
前記肺の細胞増殖性障害が、肺の悪性腫瘍又は病変によって特徴付けられる、項目55~60のいずれか一項に記載の使用。
(項目62)
前記悪性腫瘍又は病変が原発巣である、項目55~61のいずれか一項に記載の使用。
(項目63)
前記悪性腫瘍又は病変が、二次病変又は転移性病変であるか、又はそれらによって特徴付けられる、項目55~62のいずれか一項に記載の使用。
(項目64)
前記悪性腫瘍が、悪性肺新生物、癌腫、又はカルチノイド腫瘍である、項目55~63のいずれか一項に記載の使用。
(項目65)
前記肺の細胞増殖性障害が、アスベスト誘発過形成、扁平上皮化生、及び良性反応性中皮化生である、項目55~64のいずれか一項に記載の使用。
(項目66)
前記肺の細胞増殖性障害が肺癌である、項目55~65のいずれか一項に記載の使用。
(項目67)
前記肺癌が小細胞肺癌である、項目66に記載の使用。
(項目68)
前記肺癌が非小細胞肺癌である、項目66に記載の使用。
(項目69)
前記肺癌が扁平上皮癌である、項目66に記載の使用。
(項目70)
前記肺癌が腺癌である、項目66に記載の使用。
(項目71)
前記肺癌が小細胞癌である、項目66に記載の使用。
(項目72)
前記肺癌が大細胞癌である、項目66に記載の使用。
(項目73)
前記肺癌が腺扁平上皮癌である、項目66に記載の使用。
(項目74)
前記肺癌が中皮腫である、項目66に記載の使用。
(項目75)
前記細胞増殖性疾患が、原発性腫瘍によって特徴付けられ、前記原発性腫瘍が、
(A)SMARCA2/SMARCA4二重喪失を示し;かつ
(B)低分化型であり、かつ/又は上皮間葉転換(EMT)の特徴を示す、項目55~74のいずれか一項に記載の使用。
(項目76)
前記原発性腫瘍が、低いE-カドヘリン発現レベル及び高いビメンチン発現レベルを示す、項目75に記載の使用。
(項目77)
前記対象が、前記EZH2阻害剤の投与と同時に又は時間的に近接して追加の治療薬が既に投与された、又は投与されている、項目55~76のいずれか一項に記載の使用。
(項目78)
前記追加の治療薬が標準治療剤である、項目77に記載の使用。
(項目79)
前記追加の治療薬が、図式1に記載の薬剤であるか、若しくはそれを含むか、又は図式1に記載の2つ以上の薬剤の組み合わせであるか、若しくはそれを含む、項目78に記載の使用。
(項目80)
前記追加の治療薬が免疫チェックポイント阻害剤である、項目79に記載の使用。
(項目81)
前記免疫チェックポイント阻害剤が、CTLA4阻害剤、PD-1阻害剤及び/若しくはPD-L1阻害剤、LAG3阻害剤、B7-H3阻害剤、又はTim3阻害剤である、項目80に記載の使用。
(項目82)
前記免疫チェックポイント阻害剤が、イピリムマブ、チシリムマブ、AGEN-1884、ニボルマブ、ペンブロリズマブ、アテゾリズマブ、デュルバルマブ、アベルマブ、BMS-936559、AMP-224、MEDI-0680、TSR-042、BGB-108、STI-1014、KY-1003、ALN-PDL、BGB-A317、KD-033、REGN-2810、PDR-001、SHR-1210、MGD-013、PF-06801591、CX-072、IMP-731、LAG-525、BMS-986016、GSK-2831781、エノブリツズマブ、1241-8H9、DS-5573、MBG-453、又はそれらの組み合わせを含む、項目81に記載の使用。
(項目83)
前記EZH2阻害剤及び前記追加の治療薬が前記対象に連続的に投与される、項目77~82のいずれか一項に記載の使用。
(項目84)
前記EZH2阻害剤及び前記追加の治療薬が、異なる投与経路を介して異なる間隔で投与される、項目77~83のいずれか一項に記載の使用。
(項目85)
前記EZH2阻害剤が1日に2回経口投与される、項目55~84のいずれか一項に記載の使用。
(項目86)
SMARCA2及び/又はSMARCA4タンパク質の発現及び/又はSMARCA2及び/又はSMARCA4タンパク質の機能を検出することをさらに含む、項目55~85のいずれか一項に記載の使用。
(項目87)
前記SMARCA2及び/又はSMARCA4タンパク質の発現及び/又は機能が、
(a)前記対象から生体試料を得ること;
(b)前記生体試料又はその一部を、SMARCA2又はSMARCA4に特異的に結合する抗体に接触させること;及び
(c)SMARCA2又はSMARCA4に結合した抗体の量を検出すること
を含むステップによって評価される、項目86に記載の使用。
(項目88)
前記対象から得られた生体試料におけるSMARCA2タンパク質をコードする遺伝子及び/又はSMARCA4タンパク質をコードする遺伝子のゲノム変異を検出することをさらに含む、項目55~87のいずれか一項に記載の使用。
(項目89)
前記ゲノム変異が:
(a)前記対象から生体試料を得ること;
(b)前記生体試料におけるSMARCA2タンパク質又はその一部をコードする少なくとも1つのDNA配列、及び/又はSMARCA4タンパク質又はその一部をコードする少なくとも1つのDNA配列を配列決定すること;及び
(c)SMARCA2タンパク質又はその一部をコードする少なくとも1つのDNA配列、及び/又はSMARCA4タンパク質又はその一部をコードする少なくとも1つのDNA配列が、前記SMARCA2タンパク質又は前記SMARCA4タンパク質の発現及び/又は機能に影響を及ぼす変異を含むかどうかを決定すること
を含むステップによって検出される、項目88に記載の使用。
(項目90)
前記EZH2阻害剤が、ヒストン3のリシン27(H3K27)のトリメチル化を阻害する、項目55に記載の使用。
(項目91)
対象から得られた試料におけるSMARCA2及び/又はSMARCA4の機能の喪失を検出することをさらに含む、項目88又は89に記載の使用。
(項目92)
前記SMARCA2機能の喪失が、SMARCA2タンパク質をコードする遺伝子のゲノム変異に関連せず、かつ/又は前記SMARCA4機能の喪失が、SMARCA4をコードする遺伝子のゲノム変異に関連する、項目91に記載の使用。
(項目93)
前記対象がNSCLCを有する、項目91又92に記載の使用。
(項目94)
前記EZH2阻害剤が、
(タゼメトスタット)、又はその薬学的に許容される塩である、項目55~93のいずれか一項に記載の使用。
(項目95)
前記EZH2阻害剤が、
、その立体異性体、薬学的に許容される塩、及び/又は溶媒和物である、項目55~93のいずれか一項に記載の使用。
(項目96)
前記EZH2阻害剤が、
又はその薬学的に許容される塩である、項目55~93のいずれか一項に記載の使用。
(項目97)
前記EZH2阻害剤が、
、その立体異性体、薬学的に許容される塩、及び/又は溶媒和物である、項目55~93のいずれか一項に記載の使用。
(項目98)
前記EZH2阻害剤が、
、その立体異性体、薬学的に許容される塩、及び/又は溶媒和物である、項目55~93のいずれか一項に記載の使用。
(項目99)
前記EZH2阻害剤が、
(項目100)
前記EZH2阻害剤が経口投与される、項目55~93のいずれか一項に記載の使用。
(項目101)
前記EZH2阻害剤が経口錠剤として製剤化される、項目55~93のいずれか一項に記載の使用。
(項目102)
前記EZH2阻害剤が、10mg/kg/日~1600mg/kg/日の用量で投与される、項目55~93のいずれか一項に記載の使用。
(項目103)
前記EZH2阻害剤が、約100mg、約200mg、約400mg、約800mg、又は約1600mgの用量で投与される、項目55~93のいずれか一項に記載の使用。
(項目104)
前記EZH2阻害剤が約800mgの用量で投与される、項目55~93のいずれか一項に記載の使用。
(項目105)
前記EZH2阻害剤が1日2回(BID)投与される、項目55~93のいずれか一項に記載の使用。
Claims (15)
- 細胞増殖性障害の処置における使用のための、zesteホモログ2のエンハンサー(EZH2)阻害剤を含む組成物であって、前記細胞増殖性障害がSMARCA2及びSMARCA4の機能の喪失を示す細胞又は細胞集団によって特徴付けられ、ここで、前記細胞増殖性障害が原発性腫瘍により特徴付けられ、ここで前記原発性腫瘍が、
(A)SMARCA2/SMARCA4二重喪失を示し;ならびに
(B)低分化型である、及び/若しくは上皮間葉転換(EMT)の特徴を示し、
前記EZH2阻害剤が、
- 前記細胞増殖性障害が、肺の悪性腫瘍若しくは病変によって特徴付けられるか、又は、前記細胞増殖性障害が、アスベスト誘発過形成、扁平上皮化生、及び良性反応性中皮化生であるか、又は、
前記細胞増殖性障害が、肺癌である、
請求項1に記載の組成物。 - 前記細胞増殖性障害が、幹細胞由来、幹様細胞由来、若しくは前駆細胞由来によって特徴付けられる、請求項1または2に記載の組成物。
- 前記悪性腫瘍若しくは病変が原発巣であるか、又は
前記悪性腫瘍若しくは病変が、二次病変若しくは転移性病変であるか、若しくはそれらによって特徴付けられるか、又は
前記悪性腫瘍が、悪性肺新生物、癌腫、若しくはカルチノイド腫瘍である、請求項2に記載の組成物。 - 前記肺癌が小細胞肺癌であるか、又は
前記肺癌が非小細胞肺癌であるか、又は
前記肺癌が扁平上皮癌であるか、又は
前記肺癌が腺癌であるか、又は
前記肺癌が小細胞癌であるか、又は
前記肺癌が大細胞癌であるか、又は
前記肺癌が腺扁平上皮癌であるか、又は
前記肺癌が中皮腫である、請求項2に記載の組成物。 - 対象が、前記EZH2阻害剤の投与と同時に又は時間的に近接して追加の治療薬が既に投与された、又は投与されている、請求項1~5のいずれか一項に記載の組成物。
- 前記追加の治療薬が免疫チェックポイント阻害剤である、請求項6に記載の組成物。
- 前記使用が、
SMARCA2及びSMARCA4タンパク質の発現ならびに/又はSMARCA2及びSMARCA4タンパク質の機能、あるいは
前記対象から得られた生体試料における前記SMARCA2をコードする遺伝子及び前記SMARCA4タンパク質をコードする遺伝子のゲノム変異
を検出することをさらに含む、請求項1~7のいずれか一項に記載の組成物。 - 肺の細胞増殖性障害を処置することを必要とする対象の肺の細胞増殖性障害を処置することにおいて使用するための、zesteホモログ2のエンハンサー(EZH2)阻害剤を含む組成物であって、前記使用が、治療有効量の前記zesteホモログ2のエンハンサー(EZH2)阻害剤を前記対象に投与することを含み、ここで、前記細胞増殖性障害が原発性腫瘍により特徴付けられ、ここで前記原発性腫瘍が、
(A)SMARCA2/SMARCA4二重喪失を示し;ならびに
(B)低分化型である、及び/若しくは上皮間葉転換(EMT)の特徴を示し、
前記EZH2阻害剤が、
- 前記肺の細胞増殖性障害が、前記肺の悪性腫瘍又は病変によって特徴付けられる、
請求項9に記載の組成物。 - 前記悪性腫瘍若しくは病変が原発巣であるか、又は
前記悪性腫瘍若しくは病変が、二次病変若しくは転移性病変であるか、若しくはそれらによって特徴付けられるか、又は
前記悪性腫瘍が、悪性肺新生物、癌腫、若しくはカルチノイド腫瘍である、請求項10に記載の組成物。 - 前記肺の前記細胞増殖性障害が、アスベスト誘発過形成、扁平上皮化生、及び良性反応性中皮化生であるか、又は
前記肺の前記細胞増殖性障害が肺癌である、請求項11に記載の組成物。 - 前記肺癌が小細胞肺癌であるか、又は、
前記肺癌が非小細胞肺癌であるか、又は、
前記肺癌が扁平上皮癌であるか、又は
前記肺癌が腺癌であるか、又は、
前記肺癌が小細胞癌であるか、又は
前記肺癌が大細胞癌であるか、又は
前記肺癌が腺扁平上皮癌であるか、又は
前記肺癌が中皮腫である、請求項12に記載の組成物。 - 前記対象が、前記EZH2阻害剤の投与と同時に又は時間的に近接して追加の治療薬が既に投与された、又は投与されている、請求項9~13のいずれか一項に記載の組成物。
- 前記使用が、SMARCA2及びSMARCA4タンパク質の発現ならびに/又はSMARCA2及びSMARCA4タンパク質の機能を検出することをさらに含むか、あるいは
前記使用が、前記対象から得られた生体試料における前記SMARCA2をコードする遺伝子及び前記SMARCA4タンパク質をコードする遺伝子のゲノム変異を検出することをさらに含むか、あるいは
前記使用が、対象から得られた試料におけるSMARCA2及びSMARCA4の機能の喪失を検出することをさらに含む、請求項9~13のいずれか一項に記載の組成物。
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