JP2021168674A - 血中循環腫瘍細胞に関する方法およびアッセイ - Google Patents
血中循環腫瘍細胞に関する方法およびアッセイ Download PDFInfo
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Abstract
Description
本出願は、米国特許法第119条(e)(35 U.S.C. §119(e))の下で、2013年12月20日に提出された米国仮出願第61/918,816号、および2014年2月10日に提出された第61/937,883号の優先権を主張し、それらの内容はその全体が参照により本明細書に組み入れられる。
本発明は、米国国立衛生研究所(National Institutes of Health)によって授与された助成金番号2R01CA129933の下で、米国政府の援助を受けて行われた。米国政府は本発明において一定の権利を有する。
本明細書に記載される技術は、癌の診断および治療に関する。
血中循環腫瘍細胞(CTC)は、原発性腫瘍から剥離して血流中に入り、遠隔臓器への癌の伝播(転移)を媒介する。このため、血流中に血中循環腫瘍細胞(CTC)が存在すると、最終的には遠隔臓器への癌の伝播につながる。しかし、CTCは稀であり、血液1ミリリットル中の正常血液細胞100億個当たり、腫瘍細胞は1〜10個と推定される。そのため、それらの単離および分子的分析は大きな技術的課題となっている(Pantel et al., Nat Rev Cancer 2008 8:329-340(非特許文献1);Yu et al., J Cell Biol 2011 192:373-382(非特許文献2))。
本明細書に述べるように、本発明者らは、その発現がCTCに特徴的であるいくつかの遺伝子を同定した。特に、これらの遺伝子の発現は、原発性腫瘍細胞からCTCを分化させる。したがって、本明細書において提供されるのは、診断的および予後予測的な方法およびアッセイを含む、CTCの検出に関する方法およびアッセイである。さらに、本明細書において提供されるのは、例えば、転移を阻害することを目的とする、CTCのこれらのマーカーを標的とする癌の治療である。
本明細書に述べるように、本発明者らは、血中循環腫瘍細胞(CTC)が、ある特定の遺伝子、すなわちCTCマーカー遺伝子の発現によって特徴づけられることを発見した。これらのCTCマーカー遺伝子の発見により、CTCレベル、例えば、対象由来の試料におけるCTCレベルの検出および/または測定のための方法およびアッセイが可能になる。これらの方法およびアッセイは、CTCレベルの測定における速さおよび精度の向上をもたらすことができる。その上、これらのマーカー遺伝子の発現によってCTCが他の細胞、例えば、他の血中循環細胞および/または正常腫瘍細胞と識別されることから、CTCのレベルおよび/または転移能を低下させるためにこれらのマーカー遺伝子発現産物と結合させること、および/またはそれらの産物を阻害することによって、治療法をCTCに対して標的化することができる。
1. 試料中の血中循環腫瘍細胞(CTC)を検出する方法であって、
試料中のPC-CTCマーカー遺伝子発現産物のレベルを測定する段階;および
該マーカー遺伝子発現産物の検出レベルが参照基準レベルを上回る場合にPC-CTCが存在すると判定する段階
を含む、方法。
2. CTCが膵癌CTCである、項目1の方法。
3. 試料からCTCを単離する第1の段階をさらに含む、項目1〜2のいずれかの方法。
4. 発現産物が核酸である、項目1〜3のいずれかの方法。
5. 発現産物のレベルが、以下からなる群より選択される方法を用いて決定される、項目4の方法:
RT-PCR;定量的RT-PCR;ノーザンブロット法;マイクロアレイに基づく発現分析;次世代シークエンシング;およびRNAインサイチューハイブリダイゼーション。
6. 発現産物がポリペプチドである、項目1〜3のいずれかの方法。
7. 発現産物のレベルが、以下からなる群より選択される方法を用いて決定される、項目6の方法:
ウエスタンブロット法;免疫沈降法;酵素結合免疫吸着アッセイ(ELISA);放射線免疫アッセイ(RIA);サンドイッチアッセイ;蛍光インサイチューハイブリダイゼーション(FISH);免疫組織染色;放射性免疫測定アッセイ;免疫蛍光アッセイ;質量分析法;FACS;および免疫電気泳動アッセイ。
8. CTCマーカー遺伝子が表7;表8;または表14から選択される、項目1〜7のいずれかの方法。
9. CTCマーカー遺伝子が以下からなる群より選択される、項目1〜8のいずれかの方法:
ABI3BP;ADAMTS5;ADAMTSL1;ANG;ARSA;C1RL;C3;C4A;C4B;CCDC80;CD109;CHI3L1;CLEC3B;CMTM3;CMTM7;COL14A1;COL1A2;COL3A1;COL4A6;CSF1;DAG1;DCN;DMKN;FBLN1;FGF1;FMOD;GPC3;GPC4;HMGB1;IFNAR2;IGFBP5;IL16;LAMA4;LTBP4;MFAP1A;NID2;OGN;PDAP1;PF4;PLAT;PODN;PRELP;RSPO1;SERPING1;SLURP1;SOD3;SPARC;SPOCK2;SPON2;SULF1;SULF2;TGFB2;TGM2;THBD;THBS1;THSD4;TIMP2;TNXB;TPT1;TWSG1およびWNT4。
10. CTCマーカー遺伝子が以下からなる群より選択される、項目1〜8のいずれかの方法:
ALDH1A1;ALDH1A2;IGFBP5;KLF4;DCN;SPARC;WNT;TGFB2;VEGF;COL1A2;COL3A1;およびTIMP2。
11. CTCマーカー遺伝子が以下からなる群より選択される、項目1〜9のいずれかの方法:
ALDH1A2;IGFBP5;KLF4;DCN;およびSPARC。
12. CTCマーカー遺伝子が以下からなる群より選択される、項目1〜9のいずれかの方法:
ALDH1A2;IGFBP5;KLF4;およびDCN。
13. CTCマーカー遺伝子が以下からなる群より選択される、項目1〜9のいずれかの方法:
TPT1;HMGB1;SPON 2;SPARC;およびARSA。
14. CTCマーカー遺伝子が以下からなる群より選択される、項目1〜9のいずれかの方法:
IL6ST;ARSA;TIMP2;CD55;SULF2;ITGA6;SDC4;CDON;およびSV2A。
15. 対象における癌を治療する方法であって、CTCマーカー遺伝子標的療法の治療的有効量を対象に投与する段階を含む、方法。
16. 癌が膵癌である、項目15の方法。
17. CTCマーカー遺伝子標的療法がCTCマーカー遺伝子の阻害薬を含む、項目15〜16のいずれかの方法。
18. 阻害薬が抗体反応物である、項目17の方法。
19. 阻害薬が阻害性核酸反応物である、項目17の方法。
20. CTCマーカー遺伝子標的療法がCTCマーカー遺伝子結合性抗体反応物および化学療法薬を含む、項目15〜19のいずれかの方法。
21. 前記対象が、血液中および/または癌の間質中に存在するCTCのレベルが高い、かつ/またはCTCマーカー遺伝子のレベルが高いと判定された対象である、項目15〜20のいずれかの方法。
22. CTCマーカー遺伝子標的療法が、以下からなる群より選択されるマーカー遺伝子と結合するCTCマーカー遺伝子結合性抗体反応物を含む、項目15〜21のいずれかの方法:
IL6ST、SULF2およびSV2A。
23. 対象がCTCマーカー遺伝子標的療法による治療に反応する可能性が高いか否かを判定する方法であって、
血液中および/または癌の間質中に存在するCTCマーカー遺伝子発現産物のレベルを測定する段階;ならびに
該発現産物のレベルが参照基準レベルに比して高い場合に、対象が治療に反応する可能性が高いと判定する段階
を含む、方法。
24. 試料からCTCを単離する第1の段階をさらに含む、項目23の方法。
25. 癌が膵癌である、項目23〜24のいずれかの方法。
26. 発現産物が核酸である、項目23〜25のいずれかの方法。
27. 発現産物のレベルが、以下からなる群より選択される方法を用いて決定される、項目26の方法:
RT-PCR;定量的RT-PCR;ノーザンブロット法;マイクロアレイに基づく発現分析;次世代シークエンシング;およびRNAインサイチューハイブリダイゼーション。
28. 発現産物がポリペプチドである、項目23〜26のいずれかの方法。
29. 発現産物のレベルが、以下からなる群より選択される方法を用いて決定される、項目28の方法:
ウエスタンブロット法;免疫沈降法;酵素結合免疫吸着アッセイ(ELISA);放射線免疫アッセイ(RIA);サンドイッチアッセイ;蛍光インサイチューハイブリダイゼーション(FISH);免疫組織染色;放射性免疫測定アッセイ;免疫蛍光アッセイ;質量分析法;FACS;および免疫電気泳動アッセイ。
30. PC-CTCマーカー遺伝子が表7;表8;または表14から選択される、項目23〜29のいずれかの方法。
31. CTCマーカー遺伝子が以下からなる群より選択される、項目23〜30のいずれかの方法:
ABI3BP;ADAMTS5;ADAMTSL1;ANG;ARSA;C1RL;C3;C4A;C4B;CCDC80;CD109;CHI3L1;CLEC3B;CMTM3;CMTM7;COL14A1;COL1A2;COL3A1;COL4A6;CSF1;DAG1;DCN;DMKN;FBLN1;FGF1;FMOD;GPC3;GPC4;HMGB1;IFNAR2;IGFBP5;IL16;LAMA4;LTBP4;MFAP1A;NID2;OGN;PDAP1;PF4;PLAT;PODN;PRELP;RSPO1;SERPING1;SLURP1;SOD3;SPARC;SPOCK2;SPON2;SULF1;SULF2;TGFB2;TGM2;THBD;THBS1;THSD4;TIMP2;TNXB;TPT1;TWSG1およびWNT4。
32. CTCマーカー遺伝子が以下からなる群より選択される、項目23〜31のいずれかの方法:
ALDH1A1;ALDH1A2;IGFBP5;KLF4;DCN;SPARC;WNT;TGFB2;VEGF;COL1A2;COL3A1;およびTIMP2。
33. CTCマーカー遺伝子が以下からなる群より選択される、項目23〜31のいずれかの方法:
ALDH1A2;IGFBP5;KLF4;DCN;およびSPARC。
34. CTCマーカー遺伝子が以下からなる群より選択される、項目23〜31のいずれかの方法:
ALDH1A2;IGFBP5;KLF4;およびDCN。
35. CTCマーカー遺伝子が以下からなる群より選択される、項目23〜31のいずれかの方法:
TPT1;HMGB1;SPON 2;SPARC;およびARSA。
36. CTCマーカー遺伝子が以下からなる群より選択される、項目23〜31のいずれかの方法:
IL6ST;ARSA;TIMP2;CD55;SULF2;ITGA6;SDC4;CDON;およびSV2A。
37. 対象の治療をモニターするための方法であって、
癌治療法をそれを必要とする対象に投与する段階;
血液中および/または癌の間質中に存在するCTCマーカー遺伝子発現産物のレベルを測定する段階;ならびに
CTCマーカー遺伝子発現産物のレベルが参照基準レベルに比して低い場合に対象が反応していると判定し、CTCマーカー遺伝子発現産物が参照基準レベルに比して低くない場合に対象が治療に反応していないと判定する段階
を含む、方法。
38. 癌が膵癌である、項目37の方法。
39. 参照基準レベルが、投与する段階の前の患者における遺伝子発現産物のレベルである、項目37〜38のいずれかの方法。
40. 試料からCTCを単離する第1の段階をさらに含む、項目37〜39のいずれかの方法。
41. 発現産物が核酸である、項目37〜40のいずれかの方法。
42. 発現産物のレベルが、以下からなる群より選択される方法を用いて決定される、項目41の方法:
RT-PCR;定量的RT-PCR;ノーザンブロット法;マイクロアレイに基づく発現分析;次世代シークエンシング;およびRNAインサイチューハイブリダイゼーション。
43. 発現産物がポリペプチドである、項目37〜40のいずれかの方法。
44. 発現産物のレベルが、以下からなる群より選択される方法を用いて決定される、項目43の方法:
ウエスタンブロット法;免疫沈降法;酵素結合免疫吸着アッセイ(ELISA);放射線免疫アッセイ(RIA);サンドイッチアッセイ;蛍光インサイチューハイブリダイゼーション(FISH);免疫組織染色;放射性免疫測定アッセイ;免疫蛍光アッセイ;質量分析法;FACS;および免疫電気泳動アッセイ。
45. PC-CTCマーカー遺伝子が表7;表8;または表14から選択される、項目37〜44のいずれかの方法。
46. CTCマーカー遺伝子が以下からなる群より選択される、項目37〜45のいずれかの方法:
ABI3BP;ADAMTS5;ADAMTSL1;ANG;ARSA;C1RL;C3;C4A;C4B;CCDC80;CD109;CHI3L1;CLEC3B;CMTM3;CMTM7;COL14A1;COL1A2;COL3A1;COL4A6;CSF1;DAG1;DCN;DMKN;FBLN1;FGF1;FMOD;GPC3;GPC4;HMGB1;IFNAR2;IGFBP5;IL16;LAMA4;LTBP4;MFAP1A;NID2;OGN;PDAP1;PF4;PLAT;PODN;PRELP;RSPO1;SERPING1;SLURP1;SOD3;SPARC;SPOCK2;SPON2;SULF1;SULF2;TGFB2;TGM2;THBD;THBS1;THSD4;TIMP2;TNXB;TPT1;TWSG1およびWNT4。
47. CTCマーカー遺伝子が以下からなる群より選択される、項目37〜46のいずれかの方法:
ALDH1A1;ALDH1A2;IGFBP5;KLF4;DCN;SPARC;WNT;TGFB2;VEGF;COL1A2;COL3A1;およびTIMP2。
48. CTCマーカー遺伝子が以下からなる群より選択される、項目37〜46のいずれかの方法:
ALDH1A2;IGFBP5;KLF4;DCN;およびSPARC。
49. CTCマーカー遺伝子が以下からなる群より選択される、項目37〜46のいずれかの方法:
ALDH1A2;IGFBP5;KLF4;およびDCN。
50. CTCマーカー遺伝子が以下からなる群より選択される、項目37〜46のいずれかの方法:
TPT1;HMGB1;SPON 2;SPARC;およびARSA。
51. CTCマーカー遺伝子が以下からなる群より選択される、項目37〜46のいずれかの方法:
IL6ST;ARSA;TIMP2;CD55;SULF2;ITGA6;SDC4;CDON;およびSV2A。
血中循環腫瘍細胞(CTC)は、原発性腫瘍から剥離して血流中に入り、遠隔臓器への癌の血行性伝播を媒介する。膵癌マウスモデルを用いて、腫瘍エピトープに非依存的にCTCを単離するためにマイクロ流体デバイスを適用し、これらを単細胞RNAシークエンシングに供した。CTCは、原発性腫瘍および癌細胞株とは異なる複数のサブセットへとクラスター化した。増殖シグネチャーは概ね少なかったが、CTCは、MAPK、ならびにWNT、TGF-β、ニュートロフィン、Toll様受容体およびB細胞受容体シグナル伝達経路に関してエンリッチされていた。CTCは、幹細胞関連遺伝子Aldh1a2の発現に関して高度にエンリッチされていた。それらによるIgfbp5およびKlf4の事実上普遍的な発現は、上皮/間質境界に局在した原発性腫瘍細胞のサブセットと相関しており、これはCTCに上皮マーカーおよび間葉マーカーの両方が存在することに一致する。DenおよびSparcを含む間質由来細胞外マトリックスタンパク質のCTC発現が非常に高度であることにより、転移への微小環境の寄与が指し示され、かつ予想外の治療標的が同定される。
膵管腺癌(PDAC)は、米国における癌による死因の第4位であり、5年時の全生存率は6%である(Society, 2013)。この癌の高い高い死亡率は、広範な転移を招く腫瘍細胞の急速な播種から来ている。局所組織およびリンパ管への浸潤は早期PDACでも明白であり、血流中の血中循環腫瘍細胞(CTC)の存在は、遠隔臓器への癌の伝播を最終的に招く。CTCは稀であり、血液1ミリリットル中の正常血液細胞10億個当たり、腫瘍細胞は1〜10個と推定される。そのため、それらの単離および分子的分析は大きな技術的課題となっている(Pantel et al., 2008;Yu et al., 2011)。血行性転移におけるそれらの役割を考慮すると、CTC集団は転移前駆細胞に関してエンリッチされている可能性が高く、それらの分析により、有望な治療標的が同定され、ならびに膵癌の早期検出の機会がもたらされる可能性がある。
マウス膵臓CTCの単離.CTCの単離のために全血標本に直接適用される一体型マイクロ流体細胞分離プラットフォームであるCTC-iChip(Ozkumur et al., 2013)を、本明細書に記載された実験に用いた。これは、血球、血小板および血漿からのすべての有核細胞(白血球(WBC)およびCTC)の流体力学的サイズに基づく分離を最初に行い、続いて単一の流線内の有核細胞の慣性集束と組み合わせることで、高効率のインライン式磁気選別を達成する。腫瘍エピトープはばらつきが大きいが、WBC細胞表面マーカーは十分に確立されている;磁気結合抗WBC抗体をこの非常にハイスループットのマイクロ流体細胞分離デバイスに適用することにより、それ故、大多数のWBCが除外されて、タグ標識のない少数のCTCが明らかになる(図1A)。CTC-iChipをマウス造血細胞の枯渇用に適合化して、KPC膵癌マウスモデルに適用した。このPDACモデルでは、かなりの数のCTCが生じる(Rhim et al., 2012;Yu et al., 2012)。WBC当たり100個の抗CD45ビーズを用いた全血標識により、正常マウス、同所性腫瘍担持マウス、および遺伝子操作されたKPCマウスにおいて、103を上回る枯渇が達成された(図1Bおよび4A〜4C)。
本明細書に記載されたのは、単細胞RNAシークエンシングを用いた、CTCの組成および多様性の詳細な分析である。合計すると、高品質トランスクリプトームが93個のマウス膵臓単一CTCで達成され、それらを、条件を合わせた原発性腫瘍由来の20個の単細胞、ならびにバルク腫瘍調製物、ならびに同じマウス膵臓腫瘍モデルから樹立された16個の細胞と比較した。ヒトPDACによく一致するマウスモデルの使用により、CTCと同時に単離された原発性腫瘍標本と比較することが可能であった。KPCマウスモデルにおける共通のKras/Trp53遺伝的動因を考慮することで、個々のマウスにおける、および異なる動物間のCTC不均一性を検討することも可能であった。さらに、CTC-iChip技術の使用により、タグ標識のないCTCをそれらの細胞表面エピトープにかかわらず選択することが可能になり、それ故に腫瘍マーカー特異的な細胞精製物に付随するバイアスを回避することができた。総合すると、これらの観察所見には以下が含まれる:1.CTCが、主要な「古典的CTC」グループ、および血小板由来マーカーまたは増殖シグネチャーを特徴とする他のグループを含む複数のサブセットにクラスター化すること;2.個々のマウス腫瘍はこれらのクラスターのそれぞれに合致するCTCを生じうるが、それらに共通の遺伝的動因があるにもかかわらず、個々のマウスに由来するCTCに特有のパターンがあること;3.事実上すべての古典的CTCが有する共通のマーカーには、上皮マーカーおよび間葉マーカーの両方、Aldh1a2幹細胞マーカー、ならびに原発性腫瘍の上皮/間質境界に局在する病巣を特定する2種の高発現転写物(Igfbp5およびKlf4)が含まれること;ならびに4.ほぼすべての古典的CTCが共通して有する最も高度にエンリッチされているCTC特異的転写物は、腫瘍間質区画に付随する細胞外マトリックスタンパク質をコードすること。
マウスおよび細胞株.これらの実験に用いた膵癌を有するマウスは、以前に記載された通り(Bardeesy et al., 2006)、Pdx1、LSL-KrasG12D、およびTrp53lox/+またはTrp53lox/loxによって作動されるCreを発現する。EGFP膵臓系列タグ標識KPCマウスは、mT/mGマウス(Jackson Laboratory‐Gt(ROSA)26Sortm4(ACTB-tdTomato,-EGFP)Luo/J)を、KPCマウス作製のための交配ペアと交配させることによって作製した。正常FVBマウスはJackson Laboratoryから購入した。マウスの飼育および手順はすべて、MGH SRACにより承認されたプロトコールの下で行った。
マウスおよび細胞株.これらの実験に用いた膵癌を有するマウスは、以前に記載された通り(Bardeesy et al., 2006)、Pdx1、LSL-KrasG12D、およびTrp53lox/+またはTrp53lox/loxによって作動されるCreを発現する(その他の場合はKPCと称する)。EGFP膵臓系列タグ標識KPCマウスは、mT/mGマウス(Jackson Laboratory‐Gt(ROSA)26Sortm4(ACTB-tdTomato,-EGFP)Luo/J)を、KPCマウス作製のための交配ペアと交配させることによって作製した。正常FVBマウスはJackson Laboratoryから購入した。マウスの飼育および手順はすべて、MGH SRACにより承認されたプロトコールの下で行った。
と定義され、式中、
は標準正規分布の累積分布関数である。クラスターに関するM統計量の分布の平均値がクラスターの収集のためのM統計量の分布の平均値と等しいという帰無仮説に関してp値を計算するために、本発明者らは
とした。注目されることとして、ジャックナイフの代わりとして同じデータに対してブートストラップを行ったところ、同様の結果が得られた(非提示データ)。
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マウス膵臓CTCの比較分析により、60種の細胞外タンパク質のエンリッチメントが指し示された(表6)。ヒト血中循環膵臓腫瘍細胞におけるこれらの特定のバイオマーカーおよび治療標的の評価に着手し、ヒト膵臓CTCにおける最も存在量の多い標的を示している(図7)。これらは可能性のあるバイオマーカーを表しているだけでなく、腫瘍細胞の外表面にあるタンパク質というそれらの性質を考慮すれば、それらは治療標的でもある。表6の細胞外タンパク質は、例えば、癌を治療するために、抗体ベースの治療薬(例えば、HER2に対するトラスツズマブ、EGFRに対するセツキシマブ、およびVEGFに対するベバシズマブ)によって標的化することができる。
表9に特定されている標的のほとんどは分泌性因子であり、細胞表面タンパク質としてアノテーションが行われた遺伝子の分析については表14にまとめた。
1.IL6ST‐IL6、LIF、CNTFおよびオンコスタチンMに対するシグナル伝達物質。
a.下流でのSTAT3活性化のために重要
b.IL6受容体およびIL6に対する抗体は、癌を含むヒト疾患に対して開発されている
2.SULF2-スルファターゼは6-O-硫酸基を除去することによってヘパリン硫酸を修飾する
a.癌の進行および転移において発現がエンリッチされる
b.スルファターゼ活性に対する薬物が開発され、肝癌モデルにおいて活性が試験されている
3.SV2Aシナプス小胞糖タンパク質は神経内分泌細胞において高値である。
a.神経内分泌細胞のマーカーであり、ヒト膵癌の上皮間質境界に認められる
b.癌における神経内分泌分化の共通の特徴であり、より悪性度の高い疾患の前兆となる
血中循環腫瘍細胞(CTC)は、原発性腫瘍から剥離して血流中に入り、遠隔臓器への癌の血行性伝播を媒介する。それらの組成を明確にするために、CTCのゲノムワイド発現プロファイルを、膵癌のマウスモデルにおける条件を合わせた原発性腫瘍と比較し、エピトープ非依存的なマイクロ流体捕捉を用いて個々のCTCを単離し、その後に単細胞RNAシークエンシングを行った。CTCは原発性腫瘍由来のものと腫瘍由来細胞株に由来するもので別々にクラスター化し、増殖シグネチャーが少ないこと、Aldh1a2のエンリッチメント、上皮マーカーおよび間葉マーカーの混合型発現、ならびに上皮-間質境界面でエンリッチされる遺伝子転写物であるIgfbp5の発現を示した。マウスならびにヒトの膵臓CTCは、SPARCを含む間質由来細胞外マトリックス(ECM)タンパク質の極めて高度の発現を示し、癌細胞におけるそのノックダウンにより、細胞遊走および浸潤性が抑制された。間質ECM遺伝子のCTCによる異常発現は、癌の遠隔臓器への伝播のための微小環境シグナルへのそれらの寄与を提示するものである。
本明細書に記載されたのは、単細胞RNA-seqを用いた、膵癌におけるCTCの組成および多様性の詳細な分析である。高品質トランスクリプトームが93個のマウス膵臓単一CTCで達成され、それらを、条件を合わせた原発性腫瘍由来のバルク調製物および単細胞調製物、ならびに同じマウス膵臓腫瘍モデルから樹立された不死化細胞株と比較した。KPCマウスモデルの使用により、同時に単離された原発性腫瘍標本とCTCを比較することが可能になり、かつ、同じKras/Trp53遺伝的原因を共通に有する複数のマウス間でCTC不均一性を検討することも可能になった。単離されたCTCが多数であること、およびこれらの細胞から単離されたRNAが高品質であることは、正常な血液成分を効果的に枯渇させ、タグ標識のないCTCを濃縮し、かつ単細胞操作を可能にするという、CTC-iChip技術の有用性を反映している。さらに、その細胞表面エピトープにかかわらずCTCが精製されることにより、EpCAMなどの一般的な上皮マーカーの発現に基づくそれらの精製につきまとうバイアスも回避される。
Claims (51)
- 試料中の血中循環腫瘍細胞(CTC)を検出する方法であって、
試料中のPC-CTCマーカー遺伝子発現産物のレベルを測定する段階;および
該マーカー遺伝子発現産物の検出レベルが参照基準レベルを上回る場合にPC-CTCが存在すると判定する段階
を含む、方法。 - CTCが膵癌CTCである、請求項1記載の方法。
- 試料からCTCを単離する第1の段階をさらに含む、請求項1〜2のいずれか一項記載の方法。
- 発現産物が核酸である、請求項1〜3のいずれか一項記載の方法。
- 発現産物のレベルが、以下からなる群より選択される方法を用いて決定される、請求項4記載の方法:
RT-PCR;定量的RT-PCR;ノーザンブロット法;マイクロアレイに基づく発現分析;次世代シークエンシング;およびRNAインサイチューハイブリダイゼーション。 - 発現産物がポリペプチドである、請求項1〜3のいずれか一項記載の方法。
- 発現産物のレベルが、以下からなる群より選択される方法を用いて決定される、請求項6記載の方法:
ウエスタンブロット法;免疫沈降法;酵素結合免疫吸着アッセイ(ELISA);放射線免疫アッセイ(RIA);サンドイッチアッセイ;蛍光インサイチューハイブリダイゼーション(FISH);免疫組織染色;放射性免疫測定アッセイ;免疫蛍光アッセイ;質量分析法;FACS;および免疫電気泳動アッセイ。 - CTCマーカー遺伝子が表7;表8;または表14から選択される、請求項1〜7のいずれか一項記載の方法。
- CTCマーカー遺伝子が以下からなる群より選択される、請求項1〜8のいずれか一項記載の方法:
ABI3BP;ADAMTS5;ADAMTSL1;ANG;ARSA;C1RL;C3;C4A;C4B;CCDC80;CD109;CHI3L1;CLEC3B;CMTM3;CMTM7;COL14A1;COL1A2;COL3A1;COL4A6;CSF1;DAG1;DCN;DMKN;FBLN1;FGF1;FMOD;GPC3;GPC4;HMGB1;IFNAR2;IGFBP5;IL16;LAMA4;LTBP4;MFAP1A;NID2;OGN;PDAP1;PF4;PLAT;PODN;PRELP;RSPO1;SERPING1;SLURP1;SOD3;SPARC;SPOCK2;SPON2;SULF1;SULF2;TGFB2;TGM2;THBD;THBS1;THSD4;TIMP2;TNXB;TPT1;TWSG1およびWNT4。 - CTCマーカー遺伝子が以下からなる群より選択される、請求項1〜8のいずれか一項記載の方法:
ALDH1A1;ALDH1A2;IGFBP5;KLF4;DCN;SPARC;WNT;TGFB2;VEGF;COL1A2;COL3A1;およびTIMP2。 - CTCマーカー遺伝子が以下からなる群より選択される、請求項1〜9のいずれか一項記載の方法:
ALDH1A2;IGFBP5;KLF4;DCN;およびSPARC。 - CTCマーカー遺伝子が以下からなる群より選択される、請求項1〜9のいずれか一項記載の方法:
ALDH1A2;IGFBP5;KLF4;およびDCN。 - CTCマーカー遺伝子が以下からなる群より選択される、請求項1〜9のいずれか一項記載の方法:
TPT1;HMGB1;SPON 2;SPARC;およびARSA。 - CTCマーカー遺伝子が以下からなる群より選択される、請求項1〜9のいずれか一項記載の方法:
IL6ST;ARSA;TIMP2;CD55;SULF2;ITGA6;SDC4;CDON;およびSV2A。 - 対象における癌を治療する方法であって、CTCマーカー遺伝子標的療法の治療的有効量を対象に投与する段階を含む、方法。
- 癌が膵癌である、請求項15記載の方法。
- CTCマーカー遺伝子標的療法がCTCマーカー遺伝子の阻害薬を含む、請求項15〜16のいずれか一項記載の方法。
- 阻害薬が抗体反応物である、請求項17記載の方法。
- 阻害薬が阻害性核酸反応物である、請求項17記載の方法。
- CTCマーカー遺伝子標的療法がCTCマーカー遺伝子結合性抗体反応物および化学療法薬を含む、請求項15〜19のいずれか一項記載の方法。
- 前記対象が、血液中および/または癌の間質中に存在するCTCのレベルが高い、かつ/またはCTCマーカー遺伝子のレベルが高いと判定された対象である、請求項15〜20のいずれか一項記載の方法。
- CTCマーカー遺伝子標的療法が、以下からなる群より選択されるマーカー遺伝子と結合するCTCマーカー遺伝子結合性抗体反応物を含む、請求項15〜21のいずれか一項記載の方法:
IL6ST、SULF2およびSV2A。 - 対象がCTCマーカー遺伝子標的療法による治療に反応する可能性が高いか否かを判定する方法であって、
血液中および/または癌の間質中に存在するCTCマーカー遺伝子発現産物のレベルを測定する段階;ならびに
該発現産物のレベルが参照基準レベルに比して高い場合に、対象が治療に反応する可能性が高いと判定する段階
を含む、方法。 - 試料からCTCを単離する第1の段階をさらに含む、請求項23記載の方法。
- 癌が膵癌である、請求項23〜24のいずれか一項記載の方法。
- 発現産物が核酸である、請求項23〜25のいずれか一項記載の方法。
- 発現産物のレベルが、以下からなる群より選択される方法を用いて決定される、請求項26記載の方法:
RT-PCR;定量的RT-PCR;ノーザンブロット法;マイクロアレイに基づく発現分析;次世代シークエンシング;およびRNAインサイチューハイブリダイゼーション。 - 発現産物がポリペプチドである、請求項23〜26のいずれか一項記載の方法。
- 発現産物のレベルが、以下からなる群より選択される方法を用いて決定される、請求項28記載の方法:
ウエスタンブロット法;免疫沈降法;酵素結合免疫吸着アッセイ(ELISA);放射線免疫アッセイ(RIA);サンドイッチアッセイ;蛍光インサイチューハイブリダイゼーション(FISH);免疫組織染色;放射性免疫測定アッセイ;免疫蛍光アッセイ;質量分析法;FACS;および免疫電気泳動アッセイ。 - PC-CTCマーカー遺伝子が表7;表8;または表14から選択される、請求項23〜29のいずれか一項記載の方法。
- CTCマーカー遺伝子が以下からなる群より選択される、請求項23〜30のいずれか一項記載の方法:
ABI3BP;ADAMTS5;ADAMTSL1;ANG;ARSA;C1RL;C3;C4A;C4B;CCDC80;CD109;CHI3L1;CLEC3B;CMTM3;CMTM7;COL14A1;COL1A2;COL3A1;COL4A6;CSF1;DAG1;DCN;DMKN;FBLN1;FGF1;FMOD;GPC3;GPC4;HMGB1;IFNAR2;IGFBP5;IL16;LAMA4;LTBP4;MFAP1A;NID2;OGN;PDAP1;PF4;PLAT;PODN;PRELP;RSPO1;SERPING1;SLURP1;SOD3;SPARC;SPOCK2;SPON2;SULF1;SULF2;TGFB2;TGM2;THBD;THBS1;THSD4;TIMP2;TNXB;TPT1;TWSG1およびWNT4。 - CTCマーカー遺伝子が以下からなる群より選択される、請求項23〜31のいずれか一項記載の方法:
ALDH1A1;ALDH1A2;IGFBP5;KLF4;DCN;SPARC;WNT;TGFB2;VEGF;COL1A2;COL3A1;およびTIMP2。 - CTCマーカー遺伝子が以下からなる群より選択される、請求項23〜31のいずれか一項記載の方法:
ALDH1A2;IGFBP5;KLF4;DCN;およびSPARC。 - CTCマーカー遺伝子が以下からなる群より選択される、請求項23〜31のいずれか一項記載の方法:
ALDH1A2;IGFBP5;KLF4;およびDCN。 - CTCマーカー遺伝子が以下からなる群より選択される、請求項23〜31のいずれか一項記載の方法:
TPT1;HMGB1;SPON 2;SPARC;およびARSA。 - CTCマーカー遺伝子が以下からなる群より選択される、請求項23〜31のいずれか一項記載の方法:
IL6ST;ARSA;TIMP2;CD55;SULF2;ITGA6;SDC4;CDON;およびSV2A。 - 対象の治療をモニターするための方法であって、
癌治療法をそれを必要とする対象に投与する段階;
血液中および/または癌の間質中に存在するCTCマーカー遺伝子発現産物のレベルを測定する段階;ならびに
CTCマーカー遺伝子発現産物のレベルが参照基準レベルに比して低い場合に対象が反応していると判定し、CTCマーカー遺伝子発現産物が参照基準レベルに比して低くない場合に対象が治療に反応していないと判定する段階
を含む、方法。 - 癌が膵癌である、請求項37記載の方法。
- 参照基準レベルが、投与する段階の前の患者における遺伝子発現産物のレベルである、請求項37〜38のいずれか一項記載の方法。
- 試料からCTCを単離する第1の段階をさらに含む、請求項37〜39のいずれか一項記載の方法。
- 発現産物が核酸である、請求項37〜40のいずれか一項記載の方法。
- 発現産物のレベルが、以下からなる群より選択される方法を用いて決定される、請求項41記載の方法:
RT-PCR;定量的RT-PCR;ノーザンブロット法;マイクロアレイに基づく発現分析;次世代シークエンシング;およびRNAインサイチューハイブリダイゼーション。 - 発現産物がポリペプチドである、請求項37〜40のいずれか一項記載の方法。
- 発現産物のレベルが、以下からなる群より選択される方法を用いて決定される、請求項43記載の方法:
ウエスタンブロット法;免疫沈降法;酵素結合免疫吸着アッセイ(ELISA);放射線免疫アッセイ(RIA);サンドイッチアッセイ;蛍光インサイチューハイブリダイゼーション(FISH);免疫組織染色;放射性免疫測定アッセイ;免疫蛍光アッセイ;質量分析法;FACS;および免疫電気泳動アッセイ。 - PC-CTCマーカー遺伝子が表7;表8;または表14から選択される、請求項37〜44のいずれか一項記載の方法。
- CTCマーカー遺伝子が以下からなる群より選択される、請求項37〜45のいずれか一項記載の方法:
ABI3BP;ADAMTS5;ADAMTSL1;ANG;ARSA;C1RL;C3;C4A;C4B;CCDC80;CD109;CHI3L1;CLEC3B;CMTM3;CMTM7;COL14A1;COL1A2;COL3A1;COL4A6;CSF1;DAG1;DCN;DMKN;FBLN1;FGF1;FMOD;GPC3;GPC4;HMGB1;IFNAR2;IGFBP5;IL16;LAMA4;LTBP4;MFAP1A;NID2;OGN;PDAP1;PF4;PLAT;PODN;PRELP;RSPO1;SERPING1;SLURP1;SOD3;SPARC;SPOCK2;SPON2;SULF1;SULF2;TGFB2;TGM2;THBD;THBS1;THSD4;TIMP2;TNXB;TPT1;TWSG1およびWNT4。 - CTCマーカー遺伝子が以下からなる群より選択される、請求項37〜46のいずれか一項記載の方法:
ALDH1A1;ALDH1A2;IGFBP5;KLF4;DCN;SPARC;WNT;TGFB2;VEGF;COL1A2;COL3A1;およびTIMP2。 - CTCマーカー遺伝子が以下からなる群より選択される、請求項37〜46のいずれか一項記載の方法:
ALDH1A2;IGFBP5;KLF4;DCN;およびSPARC。 - CTCマーカー遺伝子が以下からなる群より選択される、請求項37〜46のいずれか一項記載の方法:
ALDH1A2;IGFBP5;KLF4;およびDCN。 - CTCマーカー遺伝子が以下からなる群より選択される、請求項37〜46のいずれか一項記載の方法:
TPT1;HMGB1;SPON 2;SPARC;およびARSA。 - CTCマーカー遺伝子が以下からなる群より選択される、請求項37〜46のいずれか一項記載の方法:
IL6ST;ARSA;TIMP2;CD55;SULF2;ITGA6;SDC4;CDON;およびSV2A。
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