JP2021530485A - がんを処置するための方法 - Google Patents
がんを処置するための方法 Download PDFInfo
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- JP2021530485A JP2021530485A JP2021500545A JP2021500545A JP2021530485A JP 2021530485 A JP2021530485 A JP 2021530485A JP 2021500545 A JP2021500545 A JP 2021500545A JP 2021500545 A JP2021500545 A JP 2021500545A JP 2021530485 A JP2021530485 A JP 2021530485A
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Abstract
Description
本出願は、2018年7月12日付で出願された米国仮特許出願第62/697,053号; 2018年10月26日付で出願された米国仮特許出願第62/751,129号; および2019年4月29日付で出願された米国仮特許出願第62/839,912号の米国特許法第119条(e)項の下での恩典を主張するものであり、その各々の内容は参照によりその全体が本明細書に組み入れられる。
本発明の分野は、がんの処置に関する。
本発明は、国立衛生研究所によって授与された助成金番号R01 CA193651の下で政府支援を受けてなされた。政府は本発明において一定の権利を有する。
白血病は、診断の約30%を占める最も一般的な小児がんである。2つの主要なサブタイプ; 急性リンパ芽球性白血病(ALL)および急性骨髄性白血病(AML)がある。AMLはあまり一般的ではなく、小児白血病の診断のおよそ18%を占めている。これらの白血病のタイプは成人にも発生し、AMLは高齢者でより一般的になる。2つのサブタイプの病因は、細胞系統と発生率および危険因子の疫学研究との両方に基づいてかなり異なる可能性が高い。ALLまたはAMLのような白血病と診断された患者の予後を改善するには、積極的化学療法が必要とされる。
便宜上、本明細書、実施例、および添付の特許請求の範囲において用いられるいくつかの用語および語句の意味が、以下に提供される。特に明記しない限り、または文脈から暗に示されない限り、以下の用語および語句は以下に示す意味を含む。本技術の範囲は特許請求の範囲によってのみ限定されるため、定義は、特定の態様を説明するのに助けるために提供するものであり、主張する本発明を限定する意図はない。特に定義されない限り、本明細書において用いられる全ての技術的および科学的用語は、本技術が属する分野の当業者によって一般に理解されているものと同じ意味を有する。当技術分野における用語の使用法と、本明細書において提供されるその定義との間に明らかな矛盾がある場合、本明細書内に提供される定義が優先されるものとする。
がんを処置する方法
本明細書において記載される本発明は部分的に、GSK3α阻害物質の投与を介したGSK3αの阻害がアスパラギナーゼによる処置に対して、がん細胞、例えば、白血病細胞を感受性化したという発見に関連している。具体的には、GSK3α阻害物質による処置は、アスパラギナーゼ耐性細胞を感受性化し、それらはアスパラギナーゼによる処置の影響を受けやすくなった。したがって、本発明の1つの局面は、がんを有する対象にアスパラギナーゼとGSK3αを阻害する作用物質とを投与する段階を含む、がんを処置するための方法を提供する。
本明細書において用いられる場合、「がん」は、正常な細胞制御を失い、無秩序な増殖、分化の欠如、局所組織浸潤、および転移をもたらす細胞の過剰増殖をいう。がんは組織型(例えば、それらが発生する組織)およびそれらの原発部位(例えば、がんが最初に発生する身体の位置)に基づいて分類され、がん腫、黒色腫、肉腫、骨髄腫、白血病、またはリンパ腫であることができる。「がん」は、固形腫瘍をいうこともできる。本明細書において用いられる場合、「腫瘍」という用語は、例えば、悪性型または良性型の細胞または組織の異常な増殖をいう。「がん」は転移性であることができ、これは、がん細胞がその一次起源部位から播種し、二次部位に移動したことを意味する。
非必須アミノ酸であるアスパラギンを分解する抗白血病酵素であるアスパラギナーゼは、急性リンパ芽球性白血病(ALL)を処置するために用いられる化学療法薬である。他のいくつかの血液障害を処置するために用いることもできる。アスパラギナーゼは当技術分野において、例えば、エルウィナーゼ、クリサンタスパーゼまたはL-アスパラギナーゼとしても公知である。アスパラギナーゼは、L-アスパラギンのアスパラギン酸およびアンモニアへの変換を触媒し、したがって白血病細胞から循環血中アスパラギンを奪い、これによって細胞死を引き起こす。
いくつかの態様において、本明細書において記載される方法は、本明細書において記載されるアスパラギナーゼと組み合わせて、GSK3αを阻害する作用物質を投与する段階を含む、がん(例えば、白血病、結腸がんまたは膵臓がん)を有するまたは有すると診断された対象の処置に関する。いくつかの態様において、本明細書において記載される方法は、本明細書において記載されるアスパラギナーゼを投与する段階を含むGSK3αの阻害をもたらす変異を含むがんを有するまたは有すると診断された対象の処置に関する。がんを有する対象は、医師により状態を診断する現行の方法を用いて同定することができる。この疾患を特徴付け、診断に役立つがんの症状および/または合併症は、当技術分野において周知である。例えばがん、の診断に役立ちうる検査は、血液検査および非侵襲的画像診断を含む。特定のがんの家族歴は、対象が状態を有する可能性が高いかどうかを判定するうえでも役立ち、またはがんの診断を下すうえでも役立つ。
「単位剤形」は、この用語が本明細書において用いられる場合、適切な1回の投与のための投薬量をいう。例として、単位剤形は、送達デバイス、例えば、シリンジまたは静脈内点滴バッグに配置された治療用物質の量であることができる。1つの態様において、単位剤形は、単回投与で投与される。別の態様において、2つ以上の単位剤形を同時に投与することができる。
1つの局面において、本明細書において記載される作用物質およびアスパラギナーゼは、がんの処置のために組み合わせて投与される。本明細書において用いられる「組み合わせて」投与されるとは、障害による対象の苦痛の経過中に2つ(またはそれ以上)の異なる処置(例えば、アスパラギナーゼ、およびGSK3αを阻害する作用物質、またはがん療法)が対象に送達される、例えば、対象が障害(例えば、がん)と診断された後に、かつ障害が治癒されもしくは取り除かれる前に、または他の理由で処置が中止される前に、2つまたはそれ以上の処置が送達されることを意味する。いくつかの態様において、1つの処置の送達は、第2の処置の送達が始まる時に依然として行われているので、投与という点で重複している。これは本明細書において「同時」または「同時送達」といわれることもある。他の態様において、一方の処置の送達は、他方の処置の送達が始まる前に終了する。いずれかの場合のいくつかの態様において、処置は、組み合わせた実施のためにより効果的である。例えば、第2の処置はより効果的であり、例えば、第2の処置を少なくしても同等の効果が見られるか、または第2の処置が第1の処置の非存在下で実施された場合に見られるよりも大幅に、第2の処置が症状を低減するか、または第1の処置で同様の状況が見られる。いくつかの態様において、送達は、症状の低減、または障害に関連する他のパラメータが、他方の非存在下で送達された一方の処置で観察されるものよりも大きいようなものである。2つの処理の効果は、部分的に相加的である場合、完全に相加的である場合、または相加的よりも大きい場合がある。送達は、送達された第1の処置の効果が、第2の処置が送達される時に依然として検出可能であるようなものであることができる。本明細書において記載される作用物質および少なくとも1つのさらなる治療は同時に、同じもしくは別々の組成物中で、または連続的に投与することができる。連続投与の場合、本明細書において記載される作用物質および/またはアスパラギナーゼを最初に投与することができ、さらなる作用物質を2番目に投与することができ、または投与の順序を逆にすることができる。作用物質および/または他の治療剤、手順、もしくはモダリティは、活動性障害の期間中、または寛解もしくは活動性の低い疾患の期間中に投与することができる。作用物質は、別の処置の前に、処置と同時に、処置後に、または障害の寛解中に投与することができる。
本明細書において記載される作用物質および/またはアスパラギナーゼの非経口剤形は、皮下、静脈内(ボーラス注射を含む)、筋肉内、および動脈内を含むが、これらに限定されない、さまざまな経路によって対象に投与することができる。非経口剤形の投与は、通常、混入物に対する患者の自然防御を回避するので、非経口剤形は、好ましくは、無菌であるか、または患者への投与の前に滅菌することができる。非経口剤形の例としては、注射の準備ができている溶液、注射用の薬学的に許容されるビヒクルに溶解または懸濁される準備ができている乾燥製品、注射の準備ができている懸濁液、制御放出性の非経口剤形、および乳濁液が挙げられるが、これらに限定されることはない。
本明細書において記載される局面のいくつかの態様において、作用物質および/またはアスパラギナーゼは、制御放出性または遅延放出性の手段によって対象に投与される。理想的には、医療処置での最適にデザインされた制御放出調製物の使用は、最少量の薬物を用い、最小限の時間で状態を治癒または制御することによって特徴付けられる。制御放出製剤の利点には、1) 薬物の活性延長; 2) 投薬頻度の低減; 3) 患者のコンプライアンス増大; 4) 合計薬物の使用減少; 5) 局所または全身副作用の低減; 6) 薬物蓄積の最小化; 7) 血中レベルの変動低減; 8) 処置の有効性の改善; 9) 薬物活性の増強または消失の低減; および10) 疾患または状態の制御速度の改善が挙げられる。(Kim, Cherng-ju, Controlled Release Dosage Form Design, 2 (Technomic Publishing, Lancaster, Pa.: 2000))。制御放出製剤を用いて、式(I)の化合物の作用の発現、作用の持続期間、治療ウィンドウ内の血漿中レベル、およびピーク血中レベルを制御することができる。特に、制御放出性または延長放出性の剤形または製剤を用いて、作用物質の最大の有効性を達成する一方で、薬物の過少投与(すなわち、最低治療レベルを下回る)および薬物の毒性レベルの超過の両方から起こりうる、可能性のある有害作用および安全性の問題を最小限にすることを確実にできる。
例えば、がんの処置のための、本明細書において記載される作用物質および/またはアスパラギナーゼの有効性は、当業者によって決定されることができる。しかしながら、がんの兆候もしくは症状の1つもしくは複数が有益な方法で変化する場合には、他の臨床的に認められた症状が改善され、もしくはさらに好転される場合には、または所望の応答が、例えば、本明細書において記載される方法による処置後に少なくとも10%誘導される場合には、「有効な処置」という用語が本明細書において用いられるように、処置は「有効な処置」と見なされる。有効性は、例えば、マーカー、指標、症状、および/もしくは本明細書において記載される方法によって処置される状態(例えば、がん)の発生率または適切な任意の他の測定可能なパラメータを測定することにより評価することができる。有効性は、入院によって評価されるように個体が悪化しないこと、または医学的介入の必要性(すなわち、がんの進行)によって測定することもできる。これらの指標を測定する方法は、当業者に知られており、かつ/または本明細書において記載されている。
1. がんを有する対象にアスパラギナーゼとGSK3αを阻害する作用物質とを投与する段階を含む、がんを処置するための方法。
2. 前記がんが、がん腫、黒色腫、肉腫、骨髄腫、白血病、およびリンパ腫からなるリストから選択される、項目1の方法。
3. 前記がんが固形腫瘍である、項目1の方法。
4. 前記白血病が、急性骨髄性白血病(AML)、慢性骨髄性白血病(CML)、急性リンパ性白血病(ALL)、および慢性リンパ性白血病(CLL)である、項目2の方法。
5. 前記がんがアスパラギナーゼに耐性である、項目1の方法。
6. 前記がんがアスパラギナーゼに耐性ではない、項目1の方法。
7. 前記アスパラギナーゼが、L-アスパラギナーゼ(Elspar)、ペグアスパルガーゼ(PEG-アスパラギナーゼ; Oncaspar)、SC-PEGアスパラギナーゼ(カラスパルガーゼペゴル)、およびエルウィニアアスパラギナーゼ(エルウィナーゼ)からなる群より選択される、項目1の方法。
8. GSK3αを阻害する前記作用物質が、小分子、抗体、ペプチド、ゲノム編集システム、アンチセンスオリゴヌクレオチド、およびRNAiからなる群より選択される、項目1の方法。
9. 前記小分子が、BRD0705、BRD4963、BRD1652、BRD3731、CHIR-98014、LY2090314、AZD1080、CHIR-99021 (CT99021) HCl、CHIR-99021 (CT99021)、BIO-アセトキシム、SB216763、SB415286、NP031112、アベマシクリブ(LY2835210)、AT-9283、RGB-286638、PHA-793887、AT-7519、AZD-5438、OTS-167、9-ING-41、およびチデグルシブ(NP031112)からなる群より選択される、項目8の方法。
10. 前記小分子がBRD0705である、項目8の方法。
11. 前記RNAiがマイクロRNA、siRNA、またはshRNAである、項目8の方法。
12. GSK3αを阻害することが、GSK3αの発現レベルおよび/または活性を阻害することである、項目1の方法。
13. GSK3αの前記発現レベルおよび/または活性が、適切な対照と比較して少なくとも50%、少なくとも60%、少なくとも70%、少なくとも80%、少なくとも90%、またはそれ以上阻害される、項目12の方法。
14. 前記対象に抗がん療法が以前に実施されている、項目1の方法。
15. 前記対象に抗がん療法が以前に実施されていない、項目1の方法。
16. 投与する段階の前に、がんを有すると対象を診断する段階をさらに含む、項目1〜15のいずれかの方法。
17. 投与する段階の前に、がんを有すると対象を診断するアッセイ法から結果を受け取る段階をさらに含む、項目1〜15のいずれかの方法。
18. GSK3αの阻害をもたらす変異を含むがんを有する対象に、アスパラギナーゼを投与する段階を含む、がんを処置するための方法。
19. 前記変異が、がん細胞においてWNTシグナル伝達経路の活性化をもたらす、項目18の方法。
20. 前記変異が、R-スポンジン1 (RSPO1)、R-スポンジン2 (RSPO2)、R-スポンジン3 (RSPO3)、R-スポンジン4 (RSPO4)、リングフィンガータンパク質43 (RNF43)、およびグリコーゲンシンターゼキナーゼ3α(GSK3A、より一般的にはGSK3αと呼ばれる)からなる群より選択される遺伝子中に存在する、項目18の方法。
21. 前記変異が、R-スポンジン1 (RSPO1)、R-スポンジン2 (RSPO2)、R-スポンジン3 (RSPO3)、R-スポンジン4 (RSPO4)、リングフィンガータンパク質43 (RNF43)、およびグリコーゲンシンターゼキナーゼ3α(GSK3A、より一般的にはGSK3αと呼ばれる)からなる群より選択される遺伝子の発現を変化させる、項目18の方法。
22. 前記がんが、がん腫、黒色腫、肉腫、骨髄腫、白血病、またはリンパ腫からなるリストから選択される、項目18の方法。
23. 前記がんが固形腫瘍である、項目18の方法。
24. 前記がんが結腸がんまたは膵臓がんである、項目18の方法。
25. 前記がんが転移性である、項目18の方法。
26. 投与の前に、対象が、GSK3αの阻害をもたらす変異を含むがんを有するとして同定される、項目18の方法。
27. 前記変異が、前記対象から得られた生体サンプルにおいて同定される、項目26の方法。
28. 前記生体サンプルが組織サンプルまたは血液サンプルである、項目27の方法。
29. 前記がんががん療法に耐性である、項目1または18の方法。
30. 前記がんががん療法後に再発したものである、項目1または18の方法。
31. 前記がん療法が、化学療法、放射線療法、免疫療法、手術、ホルモン療法、幹細胞療法、標的療法、遺伝子療法、および精密療法である、項目29または30の方法。
32. a. がんを有する対象から生体サンプルを得る段階;
b. 該サンプルをアッセイし、GSK3αの阻害をもたらす変異を有するとしてがんを同定する段階; および
c. GSK3αの阻害をもたらす変異を有するがんを有するとして同定された対象に、アスパラギナーゼを投与する段階
を含む、がんを処置する方法。
33. a. GSK3αの阻害をもたらす変異を有するがんを有するとして対象を同定するアッセイ法の結果を受け取る段階; および
b. GSK3αの阻害をもたらす変異を有するがんを有するとして同定された対象に、アスパラギナーゼを投与する段階
を含む、がんを処置する方法。
34. 前記がんが固形腫瘍である、項目32および33の方法。
35. 前記がんが結腸がんまたは膵臓がんである、項目32および33の方法。
36. 前記がんが転移性である、項目32および33の方法。
37. 前記生体サンプルが組織サンプルまたは血液サンプルである、項目32および33の方法。
アスパラギナーゼ処理白血病細胞の適合性を促進する分子経路を同定するために、アスパラギナーゼ耐性であるT-ALL細胞株CCRF-CEMにおいてゲノムワイドCRISPR/Cas9機能喪失遺伝子スクリーニングを実施した(図5)。ドロップアウトスクリーニングの条件は、アスパラギンを合成する酵素であるアスパラギンシンテターゼ(ASNS)を標的にする陽性対照ガイドRNAを用いて最適化された(図6)6。
細胞株および細胞培養。 293T細胞、T-ALL細胞株、AML細胞株およびB-ALL細胞株はATCC (Manassas, VA, USA)、DSMZ (Braunschweig, Germany)、the A. Thomas Look laboratory (Boston, MA, USA)またはAlex Kentsis研究所(New York, NY, USA)から入手し、10%もしくは20%ウシ胎仔血清(FBS, Sigma-Aldrich, Saint Louis, MO)またはTET系承認済みFBS (Clontech, Mountain View, CA)および1%ペニシリン/ストレプトマイシン(Thermo Fisher Scientific)を含むDMEM、RPMI 1640またはMEMα(Thermo Fisher Scientific)中37℃、5% CO2で培養した。健常ドナーの動員末梢血由来ヒトCD34+前駆細胞はFred Hutchinson Cancer Research Center (Seattle, WA, USA)(例えばワールドワイドウェブsharedresources.fredhutch.org/products/cd34-cellsで見つけられる)から入手した。CD34+前駆細胞は、20% FBSならびに各50 ng/mlの終濃度まで組み換えヒトインターロイキン-3 (R&D systems, Minneapolis, MN)、組み換えヒトインターロイキン-6 (R&D systems, Minneapolis, MN)および組み換えヒト幹細胞因子(R&D systems, Minneapolis, MN)を補充したIMDM (Thermo Fisher Scientific)中で培養した。
を用いてPCR増幅し、QIAquick PCR精製Kit (Qiagen)を用いてPCR精製し、MGH CCIB DNA Core施設にて次世代「CRISPR配列決定」を(例えば、ワールドワイドウェブdnacore.mgh.harvard.edu/new-cgi-bin/site/pages/crispr_sequencing_main.jspで見つけられる)を実施した。CrispRVariantsLite v1.1を用いて切断効率を評価した6。
細胞(ウェルあたり25,000個)を96ウェルプレート中の完全増殖培地100 μlに播種し、化学療法剤またはビヒクルとともにインキュベートした。T-ALL細胞を48時間ごとに1:5の比率で分割した。手短に言えば、表示の用量の化学療法薬またはビヒクルを補充した新鮮培地80 μlと細胞20 μlを混合した。上記のようにAML細胞を72時間ごとに分割した。製造元の指示にしたがって、トリパンブルー生体色素染色(Invitrogen)に基づき生存細胞をカウントすることによって細胞生存率を評価した。化学療法薬にはPEG-アスパラギナーゼ(「オンカスパー(oncaspar)」, Shire, Lexington, MA)、デキサメタゾン(Sigma-Aldrich)、ビンクリスチン(Selleckchem, Houston, TX)、ドキソルビシン(Sigma-Aldrich)、6-メルカプトプリン(Abcam, Cambridge, UK)、CHIR99021 (Selleckchem)、ボルテゾミブ(Selleckchem)、ラパマイシン(Selleckchem)、RAD001 (Selleckchem)、AZD2014 (Selleckchem)、およびWnt3A (R&D systems, Minneapolis, MN)を含めた。BRD0705およびBRD0731は記載されている15ように合成された。製造元の指示にしたがいCaspase Glo 3/7 Assay (Promega, Madison, WI)を用いてカスパーゼ3/7活性を評価した。
RNeasyキット(Qiagen)を用いてRNAを単離し、SuperScript III第一鎖cDNA合成キット(Thermo Fisher Scientific)を用いてcDNAを作製した。Power SYBR(登録商標) Green PCR Master Mix (Thermo Fisher Scientific)および7500リアルタイムPCRシステム(Applied Biosystems)を用いてqRT-PCRを実施した。使用したプライマーは次の通りであった。
序論
結腸直腸がん(CRC)は、依然として米国でがんによる死亡原因の第2位であり、転移性疾患を有する患者の転帰は悲惨である(Siegel et al., 2017; Siegel et al., 2019)。CRCの推定96%には、標準的なWnt /β-カテニンシグナル伝達を活性化する変異があり(Yaeger et al., 2018)、これらの変異は腸の悪性転換を促進する(Cheung et al., 2010; Su et al., 1992)。この経路の治療的阻害についての説得力のある理論的根拠にもかかわらず(Dow et al., 2015)、発がん性β-カテニン転写を直接阻害することは困難である(Nusse and Clevers, 2017)。CRCのおよそ15%が、染色体内R-スポンジン(RSPO)再配列およびRNF43変異のような、Wntシグナル伝達のリガンド依存性活性化を推進する変異を有するという発見(Giannakis et al., 2014; Han et al., 2017; Hao et al., 2012; Koo et al., 2012; Seshagiri et al., 2012)は、Wntリガンド活性の治療的阻害にかなりの関心を呼び起こした。これは薬理学的にはるかに扱いやすく、Wntリガンド誘導性のWnt経路活性化を標的にするいくつかの治療アプローチが開発されている[(Nusse and Clevers, 2017)に概説されている]。しかしながら、Wntリガンド活性を阻害すると、病的骨折を伴う重大な骨毒性が生じる(Tan et al., 2018)。これは、Wntリガンドの生殖細胞変異によっても引き起こされる狙い通りの毒性である(Fahiminiya et al., 2013; Zheng et al., 2012)。この毒性を軽減するための努力が進行中であるが、Wntシグナル伝達の阻害が、がん治療のための十分に好ましい治療指数を有するかどうかは、不明なままである。
GSK3上流のWnt経路の活性化はアスパラギナーゼ過感受性を誘導する
リガンド誘導性のWnt経路活性化がCRCにおいてアスパラギナーゼ過感受性を誘導するかどうかを試験するために、本発明者らはヒトAPC変異体CRC細胞株HCT-15およびSW-480から始めた(Barretina et al., 2012; Gayet et al., 2001)。これらの細胞株は両方ともアスパラギナーゼ単剤療法に耐性であることが証明されたが、組み換えリガンドRspo3およびWnt3aによる処理は、アスパラギナーゼに対する有意な感受性化を誘導した(図15A)。Wnt誘導性シグナル伝達はキナーゼGSK3の阻害により媒介され(Siegfried et al., 1992; Stamos et al., 2014; Taelman et al., 2010)、GSK3αとGSK3βの両方の小分子阻害物質であるCHIR-99021 (Bennett et al., 2002)によるこれらの細胞の処理は、アスパラギナーゼ感受性化を誘導するのに十分であった(図15B)。重要なことに、GSK3阻害とアスパラギナーゼの組み合わせは、正常なヒト結腸上皮に由来するCCD-841細胞に対してほとんど毒性がなかった(図15C) (Thompson et al., 1985)。
本明細書において提示された研究は、薬物耐性白血病が、アスパラギンの異化源としてGSK3依存性タンパク質ユビキチン化およびプロテアソーム分解に依存することによってアスパラギナーゼ療法に耐性があることを示す。この適応応答は、タンパク質のWnt依存性安定化(Wnt/STOP) (Hinze et al., 2019)、つまりタンパク質分解を阻害して細胞サイズを増加させるWntシグナル伝達のGSK3依存性枝によって遮断される(Acebron et al., 2014; Huang et al., 2015; Taelman et al., 2010)。本発明者らは、アスパラギナーゼ単剤療法がCRC細胞株HCT-15の細胞サイズを有意に減少させ、この効果がWntリガンドでの処理によって反転することを見出した(図18A〜18B)。アスパラギナーゼに対するWntリガンド誘導性の感受性化がWnt/STOPによって媒介されるかどうかを試験するために、本発明者らは最初に、E3ユビキチンリガーゼFBXW7の過剰発現がWnt誘導性GSK3阻害によって安定化されたタンパク質のサブセットの分解を回復するという事実を利用した(Acebron et al., 2014)。GSK3α阻害物質BRD0705と組み合わせたアスパラギナーゼのApc変異体オルガノイドに対する毒性は、野生型FBXW7の過剰発現によって反転するが、そのタンパク質基質に結合するその能力が損なわれたFBXW7 R465C点変異体対立遺伝子によっては反転しないことが分かった(図15H) (Koepp et al., 2001)。さらに、この組み合わせの毒性は、ある範囲のプロテアソーム基質のプロテアソーム分解を直接刺激するプロテアソームサブユニットPSMA4の高活性オープンゲート変異体の発現によって反転した(図15H) (Choi et al., 2016)。したがって、GSK3上流のWntシグナル伝達の活性化は、GSK3依存性タンパク質分解を阻害することによってアスパラギナーゼ感受性化を誘導する。
これらの所見のインビボ治療可能性を試験するために、Apc欠損またはRspo3融合のいずれかとともに、Krasおよびp53変異を有する三重変異体マウス腸オルガノイドを注入された免疫不全マウスにおいて皮下腫瘍を作出した。明確に測定可能な腫瘍増殖によって評価されるように、腫瘍が移植されたら、マウスをビヒクルまたは単回用量のアスパラギナーゼによる処置にランダムに割り当てた(図16A)。アスパラギナーゼはApc欠損腫瘍にはほとんど効果がなかったが、Rspo3融合腫瘍に対しては有意な治療活性があった。実際、アスパラギナーゼ療法は、Rspo3融合腫瘍の疾患進行を著しく遅らせただけでなく(図16B)、かなりの体重減少を引き起こすことなしに(図19A)、ほとんどの処置マウスで腫瘍退縮を誘導し(図16C)、無増悪生存期間を延長した(図16D)。
GSK3阻害およびアスパラギナーゼの合成致死的な相互作用を、CRC治療に用いることができることが本明細書において示される。GSK3の阻害は、Wnt誘導性シグナル伝達の重要なメディエータであり(Siegfried et al., 1992; Stamos et al., 2014; Taelman et al., 2010)、したがって、このキナーゼは上流のWnt経路変異の結果としてCRCのサブセットで内因的に阻害されると予測される。実際、Wntリガンド活性を増強するCRCの再発性発がん変化であるRspo3の過剰発現につながる染色体再配列を伴うCRC (Chartier et al., 2016; de Lau et al., 2011; Han et al., 2017; Seshagiri et al., 2012; Storm et al., 2016)は、アスパラギナーゼ単剤療法を大いにかつ選択的に感受性化することが分かった。本明細書において提示されるモデルは、Rspo2融合またはRspo受容体RNF43の変異のような、他の上流のWnt活性化変異を有する腫瘍もアスパラギナーゼ感受性であるはずと予測している。
患者由来の異種移植片
ヘルシンキ宣言にしたがいインフォームドコンセントを得て、APC変異体結腸がんを有する患者から標本を採取した(Bullman et al., 2017)。ヒト対象研究は、Dana-Farber Cancer Institute Institutional Review boardによって承認された。以下に記載するように、患者由来の異種移植片を免疫不全マウスに移植した。マウス研究は全ての規制基準に準拠しており、ボストンチルドレンズホスピタルの施設内動物管理使用委員会によって承認された。
293T細胞、結腸直腸がん細胞株、および正常結腸細胞を、ATCC (Manassas, VA, USA)、DSMZ (Braunschweig, Germany)から購入し、10%もしくは20%ウシ胎仔血清(FBS, Sigma-Aldrich, Saint Louis, MO)またはTET系承認済みFBS (Clontech, Mountain View, CA)および1%ペニシリン/ストレプトマイシン(Thermo Fisher Scientific)を含むDMEM、RPMI-1640またはLeibovitz’s L-15培地(Thermo Fisher Scientific)中で37℃、5% CO2にて培養した。
Nu/JマウスをJackson Laboratories (Bar Harbor, ME; ストック番号0007850)から購入した。7〜9週齢の雄性ヌードマウスを実験に使用し、同腹仔を個別のケージ内に保管した。マウスを実験群にランダムに割り当て、実験動物福祉局によって定義された動物管理基準に厳密にしたがって取り扱った。全ての動物作業は、ボストンチルドレンズホスピタル(BCH)の施設内動物管理使用委員会の承認を得て行われた(プロトコル番号18-09-3784R)。
レンチウイルスは、既述(Burns et al., 2018)のように、OptiMEM (Invitrogen, Carlsbad, CA)およびポリエチレンイミン(VWR, Radnor, PA)を用いてパッケージングベクターpsPAX2 (Didier Tronoからの寄贈品; addgeneプラスミド番号12260)およびVSV.G (Tannishtha Reyaからの寄贈品; addgeneプラスミド番号14888)とともに関心対象のpLKO.1プラスミドを同時トランスフェクションすることによって作製された。
レンチウイルス形質導入の前に、マトリゲルおよびオルガノイド培地を上下にピペッティングすることによって、0.95 cm2ウェルのマウス腸オルガノイドを完全に収集した。手短に言えば、破壊されたオルガノイドを300 gで5分間遠心分離し、細胞ペレットを冷0.25%トリプシン(Thermo Fisher Scientific) 250 μl中に再懸濁し、37℃で5分間インキュベートした。その後、トリプシンを、基礎オルガノイド培地750 μlを添加することによって不活性化し、遠心分離した(300 g×5分)。8 μg/mlのポリブレン(Merck Millipore, Darmstadt, Germany)を補充した濃縮レンチウイルス250 μl中に細胞を再懸濁した。レンチウイルス感染の場合、オルガノイドとウイルスの混合物を37℃、5% CO2で12時間インキュベートした。その後、オルガノイド培地750 μlをウェルに添加し、混合物を300 gで5分間遠心分離した。ペレットを氷冷マトリゲル40 μλ中に再懸濁し、マトリゲル固化後、基礎オルガノイド培地250 μlを各ウェルに添加した。抗生物質による選択は、感染24時間後に開始された。
shRNAおよび発現プラスミド
ピューロマイシン耐性を有するpLKO.1の以下のレンチウイルスshRNAベクターはBroad InstituteのRNAi Consortiumライブラリーにより作製され、Sigma-Aldrichから入手された: shLuciferase (TRCN0000072243)、shGSK3α♯1 (TRCN0000010340)、shGSK3α♯4 (TRCN0000038682)、shGSK3β♯2 (TRCN0000039564)、shGSK3β♯6 (TRCN0000010551)。
細胞(ウェルあたり100,000個)を12ウェルプレート中の完全増殖培地100 μlに播種し、化学療法剤またはビヒクルとともにインキュベートした。細胞を48時間ごとに分割し、製造元の指示にしたがって、トリパンブルー生体色素染色(Invitrogen)に基づき生存細胞をカウントすることによって細胞生存率を評価した。化学療法薬にはアスパラギナーゼ(ペグアスパルガーゼ, Shire, Lexington, MA)、CHIR99021 (Selleckchem)、組み換えヒトWnt3Aタンパク質(R&D systems, Minneapolis, MN)および組み換えヒトR-スポンジン3タンパク質(R&D systems, Minneapolis, MN)を含めた。BRD0705およびBRD3731は記載されている(Wagner et al., 2018)ように合成された。製造元の指示にしたがいCaspase Glo 3/7 Assay (Promega, Madison, WI)を用いてカスパーゼ3/7活性を評価した。
マウス腸オルガノイドにおける化学療法応答の評価のため、Apc欠損およびRspo3融合オルガノイドを基礎オルガノイド培地(ネズミWnt3A、ネズミノギンおよびヒトR-スポンジン1タンパク質を含有しない培地)中で培養した。全0.95 cm2ウェルのオルガノイドを新しいウェルに分割し、ウェルあたりおよそ25個のオルガノイドを得ることを目的とした。オルガノイドを、以前に公開されたプロトコル(O'Rourke et al., 2016)にしたがって分割した。マトリゲルおよび基礎オルガノイド培地にビヒクルまたは化学療法剤を補充し、48時間ごとに分割した。培養10日後、ウェルあたりのオルガノイド総数を光学顕微鏡によってカウントした。Axio Imager A1顕微鏡(Zeiss, Oberkochen, Germany)で100倍の対物レンズを用いて顕微鏡検査を実施し、CV-A10デジタルカメラ(Jai, Yokohama, Japan)およびCytovisionソフトウェア(Leica Biosystems, Wetzlar, Germany)を用いて画像を撮った。
細胞(ウェルあたり100,000個)を、12ウェル形式で終濃度10 U/Lのアスパラギナーゼまたは100 ng/mlのWnt3Aリガンドを含有する完全増殖培地1 mlにプレーティングした。48時間の処理後、前方散乱(FSC-H)をフローサイトメトリーによりBeckton-Dickinson LSR-II機器で評価した。
RNeasyキット(Qiagen)を用いてRNAを単離し、SuperScript III第一鎖cDNA合成キット(Thermo Fisher Scientific)を用いてcDNAを作製した。Power SYBR(登録商標) Green PCR Master Mix (Thermo Fisher Scientific)および7500リアルタイムPCRシステム(Applied Biosystems)を用いてqRT-PCRを実施した。使用したプライマーを表S2に記載する。
APC変異体ヒトCRC PDXの移植の場合、患者の腫瘍材料をPBS中に採取し、切除後24時間以内に移植のために湿った氷上に保持した。到着時、外科用メスを用いて壊死組織および支持組織を注意深く除去した。記載されている(Bullman et al., 2017)ように、およそ1 mm×1 mmの組織断片を雄性ヌードマウスの側腹領域に皮下に移植した。腸オルガノイド(Rspo3; p53; KrasまたはApc; p53; Kras)注入の場合、マウスごとに全9.5 cm2 1ウェルのオルガノイドを皮下注入した。
1500 mm3の腫瘍体積に達したマウスは図16Bおよび16Fであった。
連続測定の二群比較の場合、両側ウェルチの不等分散t検定を用いた。三群比較の場合、一元配置分散分析モデル(ANOVA)を実施し、多重比較のためにダネットの調整を用いた。2つの効果の分析のため、二元配置ANOVAモデルを構築し、2つの効果間の相互作用項を含めた。二元配置ANOVAの多重比較の事後調整には、チューキー・クラマーの調整を含めた。対数順位検定を用いて群間の生存性の差異を試験し、カプランマイヤーの方法を用いて生存曲線を構築した。棒グラフとして示されているデータは、別段の指示がない限り、最低3回の生物学的複製の平均および標準誤差(s.e.m)を表す。報告された全てのp値は両側であり、0.05未満の場合は有意と見なされる。
Claims (37)
- がんを有する対象にアスパラギナーゼとGSK3αを阻害する作用物質とを投与する段階を含む、がんを処置するための方法。
- 前記がんが、がん腫、黒色腫、肉腫、骨髄腫、白血病、およびリンパ腫からなるリストから選択される、請求項1記載の方法。
- 前記がんが固形腫瘍である、請求項1記載の方法。
- 前記白血病が、急性骨髄性白血病(AML)、慢性骨髄性白血病(CML)、急性リンパ性白血病(ALL)、および慢性リンパ性白血病(CLL)である、請求項2記載の方法。
- 前記がんがアスパラギナーゼに耐性である、請求項1記載の方法。
- 前記がんがアスパラギナーゼに耐性ではない、請求項1記載の方法。
- 前記アスパラギナーゼが、L-アスパラギナーゼ(Elspar)、ペグアスパルガーゼ(PEG-アスパラギナーゼ; Oncaspar)、SC-PEGアスパラギナーゼ(カラスパルガーゼペゴル)、およびエルウィニア(Erwinia)アスパラギナーゼ(エルウィナーゼ)からなる群より選択される、請求項1記載の方法。
- GSK3αを阻害する前記作用物質が、小分子、抗体、ペプチド、ゲノム編集システム、アンチセンスオリゴヌクレオチド、およびRNAiからなる群より選択される、請求項1記載の方法。
- 前記小分子が、BRD0705、BRD4963、BRD1652、BRD3731、CHIR-98014、LY2090314、AZD1080、CHIR-99021 (CT99021) HCl、CHIR-99021 (CT99021)、BIO-アセトキシム、SB216763、SB415286、アベマシクリブ(LY2835210)、AT-9283、RGB-286638、PHA-793887、AT-7519、AZD-5438、OTS-167、9-ING-41、チデグルシブ(NP031112)、およびAR-A014418からなる群より選択される、請求項8記載の方法。
- 前記小分子がBRD0705である、請求項8記載の方法。
- 前記RNAiがマイクロRNA、siRNA、またはshRNAである、請求項8記載の方法。
- GSK3αを阻害することが、GSK3αの発現レベルおよび/または活性を阻害することである、請求項1記載の方法。
- GSK3αの前記発現レベルおよび/または活性が、適切な対照と比較して少なくとも50%、少なくとも60%、少なくとも70%、少なくとも80%、少なくとも90%、またはそれ以上阻害される、請求項12記載の方法。
- 前記対象に抗がん療法が以前に実施されている、請求項1記載の方法。
- 前記対象に抗がん療法が以前に実施されていない、請求項1記載の方法。
- 投与する段階の前に、がんを有すると対象を診断する段階をさらに含む、請求項1〜15のいずれか一項記載の方法。
- 投与する段階の前に、がんを有すると対象を診断するアッセイ法から結果を受け取る段階をさらに含む、請求項1〜15のいずれか一項記載の方法。
- GSK3αの阻害をもたらす変異を含むがんを有する対象に、アスパラギナーゼを投与する段階を含む、がんを処置するための方法。
- 前記変異が、がん細胞においてWNTシグナル伝達経路の活性化をもたらす、請求項18記載の方法。
- 前記変異が、R-スポンジン1 (RSPO1)、R-スポンジン2 (RSPO2)、R-スポンジン3 (RSPO3)、R-スポンジン4 (RSPO4)、リングフィンガータンパク質43 (RNF43)、およびグリコーゲンシンターゼキナーゼ3α(GSK3A、より一般的にはGSK3αと呼ばれる)からなる群より選択される遺伝子中に存在する、請求項18記載の方法。
- 前記変異が、R-スポンジン1 (RSPO1)、R-スポンジン2 (RSPO2)、R-スポンジン3 (RSPO3)、R-スポンジン4 (RSPO4)、リングフィンガータンパク質43 (RNF43)、およびグリコーゲンシンターゼキナーゼ3α(GSK3A、より一般的にはGSK3αと呼ばれる)からなる群より選択される遺伝子の発現を変化させる、請求項18記載の方法。
- 前記がんが、がん腫、黒色腫、肉腫、骨髄腫、白血病、またはリンパ腫からなるリストから選択される、請求項18記載の方法。
- 前記がんが固形腫瘍である、請求項18記載の方法。
- 前記がんが結腸がんまたは膵臓がんである、請求項18記載の方法。
- 前記がんが転移性である、請求項18記載の方法。
- 投与の前に、前記対象が、GSK3αの阻害をもたらす変異を含むがんを有するとして同定される、請求項18記載の方法。
- 前記変異が、前記対象から得られた生体サンプルにおいて同定される、請求項26記載の方法。
- 前記生体サンプルが組織サンプルまたは血液サンプルである、請求項27記載の方法。
- 前記がんががん療法に耐性である、請求項1または18記載の方法。
- 前記がんががん療法後に再発したものである、請求項1または18記載の方法。
- 前記がん療法が、化学療法、放射線療法、免疫療法、手術、ホルモン療法、幹細胞療法、標的療法、遺伝子療法、および精密療法(precision therapy)である、請求項29または30記載の方法。
- a. がんを有する対象から生体サンプルを得る段階;
b. 該サンプルをアッセイし、GSK3αの阻害をもたらす変異を有するとしてがんを同定する段階; および
c. GSK3αの阻害をもたらす変異を有するがんを有するとして同定された対象に、アスパラギナーゼを投与する段階
を含む、がんを処置する方法。 - a. GSK3αの阻害をもたらす変異を有するがんを有するとして対象を同定するアッセイ法の結果を受け取る段階; および
b. GSK3αの阻害をもたらす変異を有するがんを有するとして同定された対象に、アスパラギナーゼを投与する段階
を含む、がんを処置する方法。 - 前記がんが固形腫瘍である、請求項32および33記載の方法。
- 前記がんが結腸がんまたは膵臓がんである、請求項32および33記載の方法。
- 前記がんが転移性である、請求項32および33記載の方法。
- 前記生体サンプルが組織サンプルまたは血液サンプルである、請求項32および33記載の方法。
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