JP2020522697A - 転移性疾患における、循環腫瘍細胞(ctc)の単一細胞特徴づけに基づく治療を検出する方法 - Google Patents
転移性疾患における、循環腫瘍細胞(ctc)の単一細胞特徴づけに基づく治療を検出する方法 Download PDFInfo
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Abstract
Description
連続的な癌治療の後、癌細胞の複数の亜集団が生じ、これらはそれぞれ薬物への抵抗性又は感受性を付与し得る異なる遺伝的異常を備える。組織生検ではこれらの亜集団を検出することができないが、血液の液体生検は、これらの重要な腫瘍細胞を同定し、患者の腫瘍がどのように経時的に発展してきたかを特徴づける一助とすることができる。単一細胞ゲノムプロファイリングは、癌の発展及び多様性を研究し、並びに腫瘍の発達における希少細胞の役割を理解するための、強力な新たなツールである。クローンの多様性は、浸潤、転移、及び治療への抵抗性の発展において重要な役割を果たすように運命づけられる。
本発明では、癌患者におけるアビラテロンに対する反応に関連付けられる細胞型を同定する方法であって、(a) 該患者から取得した血液試料中の有核細胞の、免疫蛍光染色及び形態的特徴づけを含む直接的分析を実施して、循環腫瘍細胞(CTC)を同定し、かつ計数すること;(b) デジタル病理パラメーターを個別に特徴づけて、該CTCの各々についてのプロファイルを作成すること、ここで、該パラメーターは、(i)核の大きさ;(ii)核のエントロピー;(iii)核小体の数;及び(iv)必要に応じて、表1に記載の他の特徴を含み;(c) 個々の細胞をCTCの亜型に分類すること;並びに(d) 該CTCの亜型中のバイオマーカーCTCを同定すること、を含み、該バイオマーカーCTCの同定が、該患者においてアビラテロンに対する反応に関連付けられる細胞型を示す、前記方法を提供する。いくつかの実施態様において、該癌は、教師なし分類から生じるCTCの亜型分類基準を用いて分類される。いくつかの実施態様において、該バイオマーカーCTCは、大きな核、高い核エントロピー、及び高頻度の核小体の特徴を有する。いくつかの実施態様において、該方法は、さらに、前記試料から該CTCを単離する工程を含む。いくつかの実施態様において、該癌は、前立腺癌である。いくつかの実施態様において、該前立腺癌は、ホルモン不応性であり、去勢抵抗性前立腺癌とも呼ばれる。ある実施態様において、該前立腺癌は、転移性ホルモン抵抗性前立腺癌であり、転移性去勢抵抗性前立腺癌(mCRPC)とも呼ばれる。
本件開示は、統合単一細胞全ゲノムCNV分析が、複数のレプリケート間で再現的なコピー数プロファイルを提供し、ARの増幅及びPTENの喪失を含む既知の局所CNV事象の存在を確認するという発見に部分的に基づいている。本件開示はさらに、全ゲノムコピー数分析を使用して、LST及びPGAを測定することによりゲノム不安定性を再現的に特徴づけることができるという発見に部分的に基づいている。本明細書に開示されるような、野生型(LNCaP)と比較してp53変異体細胞株(PC3及びVCaP)において検出されるのは最も高いゲノム不安定性である。サブクローン性CNV駆動因子の変化の頻度及び個別のCTCにおけるゲノム不安定性を細胞表現型と組合わせて理解することにより、不均一な疾患のより正確な観察、潜在的な治療反応が可能となり、かつ新規抵抗性の機構を特定することができる。
(実施例1)
Claims (64)
- 癌患者におけるアビラテロンに対する反応に関連付けられる細胞型を同定する方法であって、
(a) 該患者から取得した血液試料中の有核細胞の、免疫蛍光染色及び形態的特徴づけを含む直接的分析を実施して、循環腫瘍細胞(CTC)を同定し、かつ計数すること;
(b) デジタル病理パラメーターを個別に特徴づけて、該CTCの各々についてのプロファイルを作成すること、ここで、該パラメーターは、
(i)核の大きさ;
(ii)核のエントロピー;
(iii)核小体の数;及び
(iv)必要に応じて、表1に記載の他の特徴、を含み;
(c) 個々の細胞をCTCの亜型に分類すること;並びに
(d) 該CTCの亜型中のバイオマーカーCTCを同定すること、
を含み、該バイオマーカーCTCの同定が、該患者においてアビラテロンに対する反応に関連付けられる細胞型を示す、前記方法。 - 該細胞が、教師なし分類から生じるCTCの亜型分類基準を用いて分類される、請求項1記載の方法。
- 該バイオマーカーCTCが、大きな核、高い核エントロピー、及び高頻度の核小体の特徴を有する、請求項1又は2記載の方法。
- さらに、前記試料から該CTCを単離する工程を含む、請求項1〜3のいずれか一項記載の方法。
- 前記癌が、前立腺癌である、請求項1〜4のいずれか一項記載の方法。
- 前記前立腺癌が、ホルモン不応性である、請求項5記載の方法。
- 細胞型の存在又は不存在を決定する方法であって、該細胞型の不存在が、癌患者におけるエンザルタミドに対する反応に関連付けられ、
(a) 該患者から取得した血液試料中の有核細胞の、免疫蛍光染色及び形態的特徴づけを含む直接的分析を実施して、循環腫瘍細胞(CTC)を同定し、かつ計数すること;
(b) デジタル病理パラメーターを個別に特徴づけて、該CTCの各々についてのプロファイルを作成すること、ここで、該パラメーターは、
(i)核の大きさ;
(ii)核のエントロピー;
(iii)核小体の数;及び
(iv)必要に応じて、表1に記載の他の特徴、を含み;
(c) 個々の細胞をCTCの亜型に分類すること;並びに
(d) 該CTCの亜型中のバイオマーカーCTCの存在又は不存在を決定すること、
を含み、該バイオマーカーCTCの不存在が、該患者においてエンザルタミドに対する反応に関連付けられる細胞型の不存在を示す、前記方法。 - 該細胞が、教師なし分類から生じるCTCの亜型分類基準を用いて分類される、請求項7記載の方法。
- 該バイオマーカーCTCが、大きな核、高い核エントロピー、及び高頻度の核小体の特徴を有する、請求項7又は8記載の方法。
- さらに、前記試料から該CTCを単離する工程を含む、請求項7〜9のいずれか一項記載の方法。
- 前記癌が、前立腺癌である、請求項7〜10のいずれか一項記載の方法。
- 前記前立腺癌が、ホルモン不応性である、請求項11記載の方法。
- 薬物で治療するための癌患者を同定する方法であって、
(a) 該患者から取得した血液試料中の有核細胞の、免疫蛍光染色及び形態的特徴づけを含む直接的分析を実施して、循環腫瘍細胞(CTC)を同定し、かつ計数すること;
(b) デジタル病理パラメーターを個別に特徴づけて、該CTCの各々についてのプロファイルを作成すること、ここで、該パラメーターは、
(i)核の大きさ;
(ii)核のエントロピー;
(iii)核小体の数;及び
(iv)必要に応じて、表1に記載の他の特徴、を含み;
(c) 個々の細胞をCTCの亜型に分類すること;並びに
(d) 該CTCの亜型中のバイオマーカーCTCの存在又は不存在を決定すること、
を含み、該バイオマーカーCTCの存在が、該癌患者にアビラテロンを投与することを示すか、又は
該バイオマーカーCTCの不存在が、該癌患者にエンザルタミドを投与することを示す、前記方法。 - 該細胞が、教師なし分類から生じるCTCの亜型分類基準を用いて分類される、請求項13記載の方法。
- 該バイオマーカーCTCが、大きな核、高い核エントロピー、及び高頻度の核小体の特徴を有する、請求項13又は14記載の方法。
- さらに、前記試料から該CTCを単離する工程を含む、請求項13〜15のいずれか一項記載の方法。
- 前記癌が、前立腺癌である、請求項13〜16のいずれか一項記載の方法。
- 前記前立腺癌が、ホルモン不応性である、請求項17記載の方法。
- さらに、該癌患者にアビラテロンを投与する工程を含む、請求項13〜18のいずれか一項記載の方法。
- さらに、該癌患者にエンザルタミドを投与する工程を含む、請求項13〜18のいずれか一項記載の方法。
- 癌患者におけるアビラテロンでの治療に対する反応を予測する方法であって、
(a) 該患者から取得した血液試料中の有核細胞の、免疫蛍光染色及び形態的特徴づけを含む直接的分析を実施して、循環腫瘍細胞(CTC)を同定し、かつ計数すること;
(b) デジタル病理パラメーターを個別に特徴づけて、該CTCの各々についてのプロファイルを作成すること、ここで、該パラメーターは、
(i)核の大きさ;
(ii)核のエントロピー;
(iii)核小体の数;及び
(iv)必要に応じて、表1に記載の他の特徴、を含み;
(c) 個々の細胞をCTCの亜型に分類すること;並びに
(d) 該CTCの亜型中のバイオマーカーCTCを同定すること、を含み、
該バイオマーカーCTCの同定が、アビラテロンでの治療に対する該癌患者の反応を予測する、前記方法。 - 該細胞が、教師なし分類から生じるCTCの亜型分類基準を用いて分類される、請求項21記載の方法。
- 該バイオマーカーCTCが、大きな核、高い核エントロピー、及び高頻度の核小体の特徴を有する、請求項21又は22記載の方法。
- さらに、前記試料から該CTCを単離する工程を含む、請求項21〜23のいずれか一項記載の方法。
- 前記癌が、前立腺癌である、請求項21〜24のいずれか一項記載の方法。
- 前記前立腺癌が、ホルモン不応性である、請求項25記載の方法。
- 癌患者におけるエンザルタミドでの治療に対する反応を予測する方法であって、
(a) 該患者から取得した血液試料中の有核細胞の、免疫蛍光染色及び形態的特徴づけを含む直接的分析を実施して、循環腫瘍細胞(CTC)を同定し、かつ計数すること;
(b) デジタル病理パラメーターを個別に特徴づけて、該CTCの各々についてのプロファイルを作成すること、ここで、該パラメーターは、
(i)核の大きさ;
(ii)核のエントロピー;
(iii)核小体の数;及び
(iv)必要に応じて、表1に記載の他の特徴、を含み;
(c) 個々の細胞をCTCの亜型に分類すること;並びに
(d) 該CTCの亜型中のバイオマーカーCTCの存在又は不存在を決定すること、
を含み、該バイオマーカーCTCの不存在が、エンザルタミドでの治療に対する該癌患者の反応を予測する、前記方法。 - 該細胞が、教師なし分類から生じるCTCの亜型分類基準を用いて分類される、請求項27記載の方法。
- 該バイオマーカーCTCが、大きな核、高い核エントロピー、及び高頻度の核小体の特徴を有する、請求項27又は28記載の方法。
- さらに、前記試料から該CTCを単離する工程を含む、請求項27〜29のいずれか一項記載の方法。
- 前記癌は、前立腺癌である、請求項27〜30のいずれか一項記載の方法。
- 前記前立腺癌が、ホルモン不応性である、請求項31記載の方法。
- 癌患者におけるアビラテロンに対する反応に関連付けられる細胞型を同定する方法であって、
(a) 該患者から取得した血液試料中の有核細胞の、免疫蛍光染色及び形態的特徴づけを含む直接的分析を実施して、循環腫瘍細胞(CTC)を同定し、かつ計数すること;
(b) デジタル病理パラメーターを個別に特徴づけて、該CTCの各々についてのプロファイルを作成すること、ここで、該パラメーターは、
(i)核の大きさ;
(ii)核のエントロピー;
(iii)細胞質の大きさ;及び
(iv)必要に応じて、表1に記載の他の特徴、を含み;
(c) 個々の細胞をCTCの亜型に分類すること;並びに
(d) 該CTCの亜型中のバイオマーカーCTCを同定すること、
を含み、該バイオマーカーCTCの同定が、該患者におけるアビラテロンに対する反応に関連付けられる細胞型を示す、前記方法。 - 該細胞が、教師なし分類から生じるCTCの亜型分類基準を用いて分類される、請求項33記載の方法。
- 該バイオマーカーCTCが、大きな核、高い核エントロピー、及び大きな細胞質の特徴を有する、請求項33又は34記載の方法。
- さらに、前記試料から該CTCを単離する工程を含む、請求項33〜35のいずれか一項記載の方法。
- 前記癌が、前立腺癌である、請求項33〜36のいずれか一項記載の方法。
- 前記前立腺癌が、ホルモン不応性である、請求項37記載の方法。
- 細胞型の存在又は不存在を決定する方法であって、該細胞型の不存在が、癌患者におけるエンザルタミドに対する反応に関連付けられ、
(a) 該患者から取得した血液試料中の有核細胞の、免疫蛍光染色及び形態的特徴づけを含む直接的分析を実施して、循環腫瘍細胞(CTC)を同定し、かつ計数すること;
(b) デジタル病理パラメーターを個別に特徴づけて、該CTCの各々についてのプロファイルを作成すること、ここで、該パラメーターは、
(i)核の大きさ;
(ii)核のエントロピー;
(iii)細胞質の大きさ;及び
(iv)必要に応じて、表1に記載の他の特徴、を含み;
(c) 個々の細胞をCTCの亜型に分類すること;並びに
(d) 該CTCの亜型中のバイオマーカーCTCの存在又は不存在を決定すること、
を含み、該バイオマーカーCTCの不存在が、該患者においてエンザルタミドに対する反応に関連付けられる細胞型の不存在を示す、前記方法。 - 該細胞が、教師なし分類から生じるCTCの亜型分類基準を用いて分類される、請求項39記載の方法。
- 該バイオマーカーCTCが、大きな核、高い核エントロピー、及び大きな細胞質の特徴を有する、請求項39又は40記載の方法。
- さらに、前記試料から該CTCを単離する工程を含む、請求項39〜41のいずれか一項記載の方法。
- 前記癌が、前立腺癌である、請求項39〜42のいずれか一項記載の方法。
- 前記前立腺癌が、ホルモン不応性である、請求項43記載の方法。
- 薬物で治療するための癌患者を同定する方法であって、
(a) 該患者から取得した血液試料中の有核細胞の、免疫蛍光染色及び形態的特徴づけを含む直接的分析を実施して、循環腫瘍細胞(CTC)を同定し、かつ計数すること;
(b) デジタル病理パラメーターを個別に特徴づけて、該CTCの各々についてのプロファイルを作成すること、ここで、該パラメーターは、
(i)核の大きさ;
(ii)核のエントロピー;
(iii)細胞質の大きさ;及び
(iv)必要に応じて、表1に記載の他の特徴、を含み;
(c) 個々の細胞をCTCの亜型に分類すること;並びに
(d) 該CTCの亜型中のバイオマーカーCTCの存在又は不存在を決定すること、
を含み、該バイオマーカーCTCの存在が、該癌患者にアビラテロンを投与することを示すか、又は
該バイオマーカーCTCの不存在が、該癌患者にエンザルタミドを投与することを示す、前記方法。 - 該細胞が、教師なし分類から生じるCTCの亜型分類基準を用いて分類される、請求項45記載の方法。
- 該バイオマーカーCTCが、大きな核、高い核エントロピー、及び大きな細胞質の特徴を有する、請求項45又は46記載の方法。
- さらに、前記試料から該CTCを単離する工程を含む、請求項45〜47のいずれか一項記載の方法。
- 前記癌が、前立腺癌である、請求項45〜48のいずれか一項記載の方法。
- 前記前立腺癌が、ホルモン不応性である、請求項49記載の方法。
- さらに、該癌患者にアビラテロンを投与する工程を含む、請求項45〜50のいずれか一項記載の方法。
- さらに、該癌患者にエンザルタミドを投与する工程を含む、請求項45〜50のいずれか一項記載の方法。
- 癌患者におけるアビラテロンでの治療に対する反応を予測する方法であって、
(a) 該患者から取得した血液試料中の有核細胞の、免疫蛍光染色及び形態的特徴づけを含む直接的分析を実施して、循環腫瘍細胞(CTC)を同定し、かつ計数すること;
(b) デジタル病理パラメーターを個別に特徴づけて、該CTCの各々についてのプロファイルを作成すること、ここで、該パラメーターは、
(i)核の大きさ;
(ii)核のエントロピー;
(iii)細胞質の大きさ;及び
(iv)必要に応じて、表1に記載の他の特徴、を含み;
(c) 個々の細胞をCTCの亜型に分類すること;並びに
(d) 該CTCの亜型中のバイオマーカーCTCを同定すること、
を含み、該バイオマーカーCTCの同定が、アビラテロンでの治療に対する該癌患者の反応を予測する、前記方法。 - 該細胞が、教師なし分類から生じるCTCの亜型分類基準を用いて分類される、請求項53記載の方法。
- 該バイオマーカーCTCが、大きな核、高い核エントロピー、及び大きな細胞質の特徴を有する、請求項53又は54記載の方法。
- さらに、前記試料から該CTCを単離する工程を含む、請求項53〜55のいずれか一項記載の方法。
- 前記癌が、前立腺癌である、請求項53〜56のいずれか一項記載の方法。
- 前記前立腺癌が、ホルモン不応性である、請求項57記載の方法。
- 癌患者におけるエンザルタミドでの治療に対する反応を予測する方法であって、
(a) 該患者から取得した血液試料中の有核細胞の、免疫蛍光染色及び形態的特徴づけを含む直接的分析を実施して、循環腫瘍細胞(CTC)を同定し、かつ計数すること;
(b) デジタル病理パラメーターを個別に特徴づけて、該CTCの各々についてのプロファイルを作成すること、ここで、該パラメーターは、
(i)核の大きさ;
(ii)核のエントロピー;
(iii)細胞質の大きさ;及び
(iv)必要に応じて、表1に記載の他の特徴、を含み;
(c) 個々の細胞をCTCの亜型に分類すること;並びに
(d) 該CTCの亜型中のバイオマーカーCTCの存在又は不存在を決定すること、
を含み、該バイオマーカーCTCの不存在が、エンザルタミドでの治療に対する該癌患者の反応を予測する、前記方法。 - 該細胞が、教師なし分類から生じるCTCの亜型分類基準を用いて分類される、請求項59記載の方法。
- 該バイオマーカーCTCが、大きな核、高い核エントロピー、及び大きな細胞質の特徴を有する、請求項59又は60記載の方法。
- さらに、前記試料から該CTCを単離する工程を含む、請求項59〜61のいずれか一項記載の方法。
- 前記癌が、前立腺癌である、請求項59〜62のいずれか一項記載の方法。
- 前記前立腺癌が、ホルモン不応性である、請求項63記載の方法。
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