JP2018529698A - Ezh2阻害剤により卵巣の悪性ラブドイド腫瘍(mrto)/高カルシウム血症型の卵巣の小細胞癌(sccoht)を処置するための方法 - Google Patents
Ezh2阻害剤により卵巣の悪性ラブドイド腫瘍(mrto)/高カルシウム血症型の卵巣の小細胞癌(sccoht)を処置するための方法 Download PDFInfo
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- JP2018529698A JP2018529698A JP2018515673A JP2018515673A JP2018529698A JP 2018529698 A JP2018529698 A JP 2018529698A JP 2018515673 A JP2018515673 A JP 2018515673A JP 2018515673 A JP2018515673 A JP 2018515673A JP 2018529698 A JP2018529698 A JP 2018529698A
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Abstract
Description
本出願は、2015年9月25日に出願された米国仮特許出願第62/233,146号明細書および2015年11月6日に出願された米国仮特許出願第62/252,188号明細書に対する優先権および利益を主張し、それぞれの内容は、全体が参照によって本明細書に組み込まれる。
またはその薬学的に許容される塩を含んでいてもよい、から本質的になってもよい、またはからなってもよい。
悪性ラブドイド腫瘍(MRT)は、軟部組織において生じるまれな小児腫瘍であり、腎臓および脳においても最もよく発生する。ある悪性ラブドイド腫瘍の特徴は、SMARCB1(INI1としても知られている)の機能喪失である。INI1は、EZH2に反対して作用するクロマチンリモデラーであるSWI/SNF調節複合体の重要な構成成分である。INI1陰性腫瘍は、SWI/SNF機能が変化しており、異常で腫瘍形成性のEZH2活性をもたらす。この活性は、タゼメトスタットなどのようなEZH2の小分子阻害剤によって標的にすることができる。INI1陰性腫瘍は、一般に侵襲性であり、現在の処置はあまり役立っていない。たとえば、十分に研究されているINI1陰性腫瘍であるMRTの現在の処置は、外科手術、化学療法、および放射線療法からなり、これらは、限られた効力および有意な処置関連死亡率に結びつけられる。米国、欧州、および日本を含む主要な市場のINI1陰性腫瘍および滑膜肉腫による患者の毎年の発病は、およそ2,400件である。SMARCB1/INI1の機能喪失はまた、別のまれな侵襲性の小児腫瘍、中枢神経系の非定型奇形腫様ラブドイド腫瘍(AT/RT)においても生じる。
MRTO/SCCOHTは、子供および若い女性(診断時の平均年齢は23歳である)に影響を与える非常にまれな侵襲性の癌である。患者の65%超は、診断の2年以内に疾患により死亡する。MRTのように、これらの腫瘍は、SWI/SNF複合体サブユニット、SMARCA4の遺伝子損失によって特徴付けられる。SMARCA4陰性卵巣癌細胞は、EZH2阻害に選択的に感受性であり、IC50値は、MRT細胞において観察されるものと同様である。たとえば、SCCOHTの現在の処置は、減量外科手術およびプラチナベースの化学療法薬からなり、高い再発率を示す。鑑別診断は大まかで、3つの卵巣癌亜型を含む:顆粒膜細胞(性索間質)腫瘍、未分化胚細胞腫、および高悪性度漿液性腫瘍。標準的なヘマトキシリンおよびエオシン(H&E)染色により、SCCOHTが、横紋筋肉腫様であり、小さく、ぎっしり詰まった、単一形の、高度に増殖性で、分化が不十分な細胞がシート状に配置されていることが示されたのに対して、IHCは、SCCOHTが、タンパク質損失に至るSMARCA4遺伝子の不活性化およびSMARCA2タンパク質の非突然変異性サイレンシングによって特徴付けられることを示唆する。(たとえばKarnezis et al.,J.Pathol.2016;238:389−400、Jelinic et al.Nat Genet 2014、Witkowski et al.,Nat.Genet.2014;46:424−426、Ramos et al.Nat.Genet.2014;46:427−429、Kupryjanczyk et al.Pol.J.Pathol.2013;64:238−246を参照されたい、それぞれの内容は、全体が参照によって本明細書に組み込まれる)。本開示のいくつかの態様は、腫瘍細胞および腫瘍、たとえば、SMARCA4損失(たとえば突然変異の結果として)およびSMARCA2損失(たとえばタンパク質損失の結果として)を示すSCCOHT腫瘍が、EZH2阻害に対して感受性であり、したがって、EZH2阻害剤により有効に処置することができることを提供する。
類上皮肉腫は、すべての軟部組織肉腫の1%未満に相当する、まれな軟部組織肉腫である。類上皮肉腫は、最初、1970年にはっきりと特徴付けられた。類上皮肉腫において見つけられる最も一般的な遺伝子突然変異は、INI−1の損失である(約80〜90%において)。類上皮肉腫の2つの変種が報告された:遠位型類上皮肉腫には、より良好な予後が伴い、上部および下部遠位四肢(指、手、前腕、または足)を冒すが、近位型類上皮肉腫には、より悪い予後が伴い、近位四肢(上腕、大腿)および体幹を冒す。類上皮肉腫は、すべての年齢層で生じるが、若年成人(診断時の年齢中央値は27歳である)が最も一般的である。類上皮肉腫は、初期処置後の高い再発率に結びつけられ、生存期間の中央値は、転移性類上皮肉腫が診断された時には2年未満となる。局所再発および転移は、患者の約30〜50%において生じ、転移は、典型的に、リンパ節、肺、骨、および脳である。類上皮肉腫の処置は、処置の好ましい方法として外科的切除を含む。手術不能な腫瘍または再発後については、従来の化学療法および放射線療法が、単独でまたは組み合わせて使用されるが、成功率は比較的低い。腫瘍学者の約50%は、類上皮肉腫が化学療法非感受性であると考えている。
本開示はまた、少なくとも1つの薬学的に許容される賦形剤またはキャリアと組み合わせて、本明細書において記載される少なくとも1つのEZH2阻害剤を含む医薬組成物をも提供する。
SMARCA4陰性MRTO/SCCOHTと診断された27歳のヒト女性は、経口錠剤によって毎日二回(BID)投与した1600mgのEPIZ−6438(タゼメトスタット)での処置に成功した。腫瘍の大きさは、8週間の処置の後、ベースラインから低下し、16週間の処置の後、8週目の測定値からさらに低下した。
タゼメトスタットによるINI1およびSMARCA4陰性腫瘍の処置は、腫瘍組織におけるHeK27me3の薬力学阻害を誘導する。
アーカイブまたはベースラインホルマリン固定パラフィン包埋(FFPE)サンプルを、ゲノムDNA単離にまわした(n=25)。25のうちの18のサンプルは、ライブラリー調製および全エクソーム解析に進むのに十分なDNAを有した。18のうちの16のサンプルは、シーケンシング精度管理をパスした。SWI/SNF構成成分のシーケンシングカバレッジの中央値は、300Xよりも大きい。dbSNPにおいて同定された変異体および<5%の対立遺伝子頻度を有する変異体は、フィルターにかけて除外した。
H3K27ヒストンメチルトランスフェラーゼEZH2は、ポリコーム抑制複合体2(PRC2)の触媒構成成分であり、複数の癌型において増幅され、過剰発現され、または突然変異し、癌遺伝子としてのその機能を裏付けている。EZH2自体の遺伝子変化に加えて、他のタンパク質の遠位遺伝子変化により、EZH2活性に対して腫瘍形成が依存するようになることがある。SWItch/Sucrose Non−Fermentable(SWI/SNF)クロマチンリモデリング複合体のコア構成成分であるINI1(SNF5/SMARCB1)が欠失した細胞株および異種移植片は、選択的EZH2阻害剤タゼメトスタットの存在下において大きな感受性および持続的な退縮を示すことが確立された(EPZ‐6438、たとえば、全体が参照によって本明細書において組み込まれるKnutson et al.PNAS 2013;110:7922−7927を参照されたい)。
SCCOHT細胞株Bin−67由来のインビボ異種移植片腫瘍に18日間、タゼメトスタットを投薬した。腫瘍は、Bin−67モデルにおいて18日後にビヒクルと比較して容積において統計的有意差を示した(図18A)。EZH2標的阻害は、18日目に集めた異種移植片組織におけるH3K27me3レベルによって評価した(図18B)。それぞれのポイントは、単一の動物の腫瘍由来の総H3に対するH3K27me3の比率に相当する。
SCCOHT細胞株COV434由来のインビボ異種移植片腫瘍に28日間、タゼメトスタットを投薬した。腫瘍は、COV434モデルにおいて28日後にビヒクルと比較して容積において統計的有意差を示した(図19A)。28日目の後に、COV434異種移植片コホートの一部分を、処置なしでの腫瘍再増殖をモニターするために保存したが、再増殖はなかった。EZH2標的阻害は、28日目に集めた異種移植片組織におけるH3K27me3レベルによって評価した(図19B)。それぞれのポイントは、単一の動物の腫瘍由来の総H3に対するH3K27me3の比率に相当する。
SCCOHT株TOV112D由来のインビボ異種移植片腫瘍に毎日二回、14日間、タゼメトスタットを投薬した。腫瘍は、TOV112Dモデルにおいて14日後にビヒクルと比較して容積において統計的有意差を示した(図20A)。EZH2標的阻害は、14日目に集めた異種移植片組織におけるH3K27me3レベルによって測定した(図20B)。それぞれのポイントは、単一の動物の腫瘍由来の総H3に対するH3K27me3の比率に相当する。
Claims (27)
- その必要がある被検体において悪性ラブドイド腫瘍を処置するための方法であって、治療有効量のzeste相同体2のエンハンサー(EZH2)の阻害剤を前記被検体に投与することを含み、任意選択で、MRTは、INI1陰性、INI1欠失、または類上皮肉腫である方法。
- その必要がある被検体における卵巣の悪性ラブドイド腫瘍(MRTO)/高カルシウム血症型の卵巣の小細胞癌(SCCOHT)を処置するための方法であって、治療有効量のEZH2阻害剤を前記被検体に投与することを含む方法。
- 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、請求項1または2に記載の方法。
- 前記EZH2阻害剤が、経口投与される、請求項1〜9のいずれか一項に記載の方法。
- 前記EZH2阻害剤が、経口錠剤として製剤化される、請求項1〜10のいずれか一項に記載の方法。
- 前記EZH2阻害剤が、10mg/kg/日〜1600mg/kg/日の用量で投与される、請求項1〜11のいずれか一項に記載の方法。
- 前記EZH2阻害剤が、約100、200、400、800、または1600mgの用量で投与される、請求項12に記載の方法。
- 前記EZH2阻害剤が、約800mgの用量で投与される、請求項12に記載の方法。
- 前記EZH2阻害剤が、1日につき二回(BID)投与される、請求項1〜14のいずれか一項に記載の方法。
- 前記SCCOHTが、SMARCA4陰性である、請求項1〜15のいずれか一項に記載の方法。
- 前記被検体が、SMARCA4陰性である、請求項1〜16のいずれか一項に記載の方法。
- SMARCA4発現またはSMARCA4の機能が、
(a)前記被検体から生物学的サンプルを得ること;
(b)前記生物学的サンプルまたはその一部分をSMARCA4に特異的に結合する抗体と接触させること;および
(c)SMARCA4に結合している前記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、請求項16または17に記載の方法。 - SMARCA4発現またはSMARCA4の機能が、
(a)前記被検体から生物学的サンプルを得ること;
(b)前記生物学的サンプルまたはその一部分由来のSMARCA4タンパク質をコードする少なくとも1つのDNA配列をシーケンシングすること;ならびに
(c)SMARCA4タンパク質をコードする前記少なくとも1つのDNA配列が、前記SMARCA4タンパク質の発現および/または機能に影響を与える突然変異を含有するかどうかを決定すること
を含む、請求項16〜18のいずれか一項に記載の方法。 - 前記生物学的サンプルが、検出のそれぞれの方法において使用される同じ生物学的サンプルである、請求項18または19に記載の方法。
- SMARCA4発現またはSMARCA4の機能が、SMARCA4に結合している前記抗体の量を検出することによっておよびSMARCA4タンパク質をコードする少なくとも1つのDNA配列をシーケンシングすることによって評価される、請求項18〜20のいずれか一項に記載の方法。
- 前記被検体が、40歳未満である、請求項1〜21のいずれか一項に記載の方法。
- 前記被検体が、30歳未満である、請求項22に記載の方法。
- 前記被検体が、20歳未満である、請求項23に記載の方法。
- 前記被検体が、20歳および30歳を含めて、20〜30歳である、請求項1〜24のいずれか一項に記載の方法。
- 処置が、SCCOHT細胞の増殖を予防するおよび/または阻害することを含む、請求項1〜25のいずれか一項に記載の方法。
- その必要がある被検体においてSCCOHTを処置するための方法であって、治療有効量のタゼメトスタットを前記被検体に投与することを含み、
前記タゼメトスタットが、経口錠剤として製剤化され、
前記治療有効量が、約800mg/kgであり、前記タゼメトスタットが、1日につき二回投与される方法。
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JP2020505426A (ja) * | 2017-02-02 | 2020-02-20 | エピザイム,インコーポレイティド | 癌処置様式 |
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KR20180054793A (ko) * | 2015-09-25 | 2018-05-24 | 에피자임, 인코포레이티드 | 악성 간상소체 종양 또는 고칼슘혈증형 난소의 소세포 암을 치료하는 방법 |
CA3011186A1 (en) | 2016-01-29 | 2017-08-03 | Epizyme, Inc. | Combination therapy for treating cancer |
EP3464643A4 (en) | 2016-06-01 | 2020-04-01 | Epizyme Inc | USE OF EZH2 INHIBITORS FOR THE TREATMENT OF CANCER |
US11147819B2 (en) | 2016-06-17 | 2021-10-19 | Epizyme, Inc. | EZH2 inhibitors for treating cancer |
US11642346B2 (en) | 2017-03-31 | 2023-05-09 | Epizyme, Inc. | Combination therapy for treating cancer |
JP2020522687A (ja) | 2017-06-02 | 2020-07-30 | エピザイム,インコーポレイティド | 癌を処置するためのezh2阻害剤の使用 |
CN111093660A (zh) | 2017-09-05 | 2020-05-01 | Epizyme股份有限公司 | 用于治疗癌症的组合疗法 |
AU2020248422A1 (en) * | 2019-03-26 | 2021-11-11 | Translational Drug Development, Llc | Method of treating malignant rhabdoid tumor of the ovary and small cell cancer of the ovary of the hypercalcemic type |
CN110950834A (zh) * | 2019-11-26 | 2020-04-03 | 济南大学 | 新型eed-ezh2相互作用小分子抑制剂的确定和评价 |
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