JP2020532982A - がんの診断及び治療方法 - Google Patents
がんの診断及び治療方法 Download PDFInfo
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- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
- C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
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Abstract
Description
本出願は、ASCIIフォーマットで電子的に提出された配列表を含み、その全内容は本明細書において参照により援用される。前記ASCIIコピーは、2018年8月9日に作成され、50474−171WO2_Sequence Listing_8.09.18_ST25と命名され、大きさは1,738バイトである。
(b)工程(a)で決定されたKRAS−G13D変異の存在に基づき、個体に治療的有効量の汎RAF二量体阻害剤及びMEK阻害剤を投与すること
を含む。
(b)工程(a)で決定されたNRAS活性化変異の存在に基づき、個体に治療的有効量の汎RAF二量体阻害剤及びMEK阻害剤を投与すること
を含む。
を含む。いくつかの実施態様では、試薬は、KRAS遺伝子の全部又は一部の増幅における使用のための第1のオリゴヌクレオチド及び第2のオリゴヌクレオチドを含む。
を含む。いくつかの実施態様では、試薬は、NRAS遺伝子の全部又は一部の増幅における使用のための第1のオリゴヌクレオチド及び第2のオリゴヌクレオチドを含む。
(b)汎RAF二量体阻害剤及びPI3K阻害剤を含む治療から利益を受け得るがんを有する個体を同定するための試薬を使用するための指示書
を含む。いくつかの実施態様では、試薬は、KRAS遺伝子の全部又は一部の増幅における使用のための第1のオリゴヌクレオチド及び第2のオリゴヌクレオチドを含む。いくつかの実施態様では、PI3K阻害剤は小分子阻害剤である。いくつかの実施態様では、小分子阻害剤は、ピクチリシブ(GDC−0941)、タセリシブ(GDC−0032)、及びアルペリシブ(BYL719)、又はそれらの薬学的に許容される塩からなる群より選択される。いくつかの実施態様では、PI3K阻害剤は汎PI3K阻害剤である。いくつかの実施態様では、汎PI3K阻害剤は、ピクチリシブ(GDC−0941)又はタセリシブ(GDC−0032)、又はその薬学的に許容される塩である。いくつかの実施態様では、個体はBRAF活性化変異を有しない。
本発明は、細胞増殖性疾患(例えばがん(例えば、結腸直腸がん、卵巣がん、肺がん、膵臓がん、及び皮膚がん(例えばメラノーマ)))の治療のための診断方法、治療方法、及び組成物を提供する。本発明は、少なくとも一部は、MEK及びPI3K阻害剤が、RAS−GTP依存性機序を通じて、NRAS活性化変異又はKRAS活性化変異、特にKRAS−G13D変異を担持するがんにおいて汎RAF二量体阻害剤との共同活性を示すという発見に基づく。したがって、KRAS−G13D及びNRAS活性化変異は、汎RAF二量体阻害剤及びMEK又はPI3K阻害剤を含む治療から利益を受け得るがんを有する個体を同定する方法;汎RAF二量体阻害剤及びMEK又はPI3K阻害剤を含むがんを有する個体のための治療を選択し、汎RAF二量体阻害剤及びMEK又はPI3K阻害剤を含む療法でがんを有する個体を治療する方法において、バイオマーカー(例えば予測バイオマーカー)として使用することができる。
本明細書に記載される本発明の態様及び実施態様は、態様及び実施態様「を含む」、「からなる」及び/又は「から本質的になる」を含むことが理解されよう。本明細書で使用される場合、単数形の「a」、「an」及び「the」は、別途指示がない限り、複数形の参照を含む。
A.診断法
本発明は、汎RAF阻害剤(例えば、汎RAF二量体阻害剤)及びMEK阻害剤又はPI3K阻害剤を含む治療から利益を受け得るがん(例えば、結腸直腸がん、卵巣がん、肺がん、膵臓がん、及び皮膚がん(例えばメラノーマ))を有する個体を同定するための方法を提供する。該方法は、個体からの試料(例えば、組織試料(例えば腫瘍組織試料))をKRAS活性化変異(例えば、KRAS−G13D変異)についてスクリーニングすることを含み、ここで、試料中のKRAS活性化変異(例えば、KRAS−G13D変異)の存在は、個体を汎RAF阻害剤(例えば、汎RAF二量体阻害剤)及びMEK又はPI3K阻害剤を含む治療から利益を受け得るものとして同定する。がんを有する個体のための治療を選択するための方法も提供される。これらの方法は、個体からの試料をKRAS活性化変異(例えば、KRAS−G13D変異)についてスクリーニングする工程を同様に含み、ここで、試料中のKRAS活性化変異(例えば、KRAS−G13D変異)の存在は、個体を汎RAF阻害剤(例えば、汎RAF二量体阻害剤)及びMEK又はPI3K阻害剤を含む治療から利益を受け得るものとして同定する。がんを有する個体の治療のための治療有効性を最適化するための方法も提供され、ここで、治療は、汎RAF阻害剤(例えば、汎RAF二量体阻害剤)及びMEK阻害剤又はPI3K阻害剤を含む。汎RAF阻害剤(例えば、汎RAF二量体阻害剤)及びMEK阻害剤又はPI3K阻害剤を含む治療に対するがんを有する個体の応答性を予測するための方法がさらに提供される。これらの方法のいずれかは、個体に治療的有効量の汎RAF阻害剤(例えば、汎RAF二量体阻害剤)及びMEK又はPI3K阻害剤を、例えばKRAS活性化変異(例えば、KRAS−G13D変異)の存在に基づき、投与することをさらに含み得る。さらに、これらの方法のいずれかは、個体に治療的有効量の追加の治療剤(例えば、免疫療法剤、細胞傷害性剤、成長阻害剤、放射線療法剤、及び抗血管新生剤)を投与することをさらに含み得る。
本発明は、KRAS活性化変異(例えば、KRAS−G13D変異)の存在に基づき、治療的有効量の汎RAF阻害剤(例えば、汎RAF二量体阻害剤)及びMEK阻害剤又はPI3K阻害剤を、がん(例えば、結腸直腸がん、卵巣がん、肺がん、膵臓がん、及び皮膚がん(例えばメラノーマ))を有する個体に投与することにより、個体を治療するための方法を提供する。ある場合では、該方法は、KRAS活性化変異を有すると決定されている個体からの試料(例えば、組織試料(例えば腫瘍組織試料)をKRAS活性化変異についてスクリーニングする工程を含む。他の場合では、治療前に、個体からの試料(例えば、組織試料(例えば腫瘍組織試料)は、KRAS活性化変異についてスクリーニングされており、該試料中のKRAS活性化変異の存在は決定されている。
MEK阻害剤又はPI3K阻害剤のいずれかと組み合わせた汎RAF阻害剤での治療に応答性又は感受性である患者は同定されると、併用療法での治療、単独での治療量、又は他の治療剤と併せた治療が行われ得る。上記のように、そのような治療は、例えば、腫瘍サイズの低減又は無増悪生存(PFS)及び/若しくは全生存(OS)の増加をもたらし得る。さらに、MEK阻害剤又はPI3K阻害剤のいずれかと組み合わせた汎RAF阻害剤での治療は、好ましくは、相乗的な(又は相加作用を超える)治療的利益を患者にもたらす。好ましくは、この組み合わせ法において、MEK阻害又はPI3K阻害剤のいずれかと組み合わせた汎RAF阻害剤の少なくとも一つの投与間のタイミングは、約1か月以下、より好ましくは約2週間以下である。
MEK阻害剤又はPI3K阻害剤のいずれか及び、任意選択的に、任意の追加の治療剤と組み合わせた汎RAF阻害剤(例えば、汎RAF二量体阻害剤)は、医学行動規範と一致した方式で製剤化され、投薬され、投与される。この観点において考慮すべき要因は、治療される特定の障害(例えば、がん)、治療される特定の哺乳動物、個々の患者の臨床状態、障害の原因、薬剤送達部位、投与方法、投与日程及び医療従事者が知る他の要因を含む。例えば、汎RAF阻害剤(例えば、汎RAF二量体阻害剤)は、MEK阻害剤又はPI3K阻害剤のいずれかと同時に、任意選択的には現在障害(例えば、がん)を予防又は治療するのに使用される一又は複数の薬剤とのさらなる組み合わせで、製剤化及び/又は投与されてもよいが、その必要はない。
本明細書に記載される治療法は、概して、複数の治療剤(例えば、MEK又はPI3K阻害剤と組み合わせた汎RAF阻害剤(例えば汎RAF二量体阻害剤))を含む。
本発明は、汎RAF阻害剤(例えば、汎RAF二量体阻害剤)及びMEK阻害剤又はPI3K阻害剤を含む組み合わせが、KRAS活性化変異(例えば、KRAS−G12D、KRAS−G12C、KRAS−G12V、KRAS−G13D、KRAS−G12A、KRAS−G12R、KRAS−G12S、KRAS−G13C、KRAS−G13A、KRAS−G13R、KRAS−G13S、KRAS−G13V、KRAS−Q61H、KRAS−Q61K、KRAS−Q61E、KRAS−Q61L、KRAS−Q61P、又はKRAS−Q61R変異)又はNRAS活性化変異(例えば、NRAS−Q61R、NRAS−Q61K、NRAS−G12D、NRAS−G13D、NRAS−G12S、NRAS−G12C、NRAS−G12V、NRAS−G12A、NRAS−G12R、NRAS−G13C、NRAS−G13A、NRAS−G13R、NRAS−G13S、NRAS−G13V、NRAS−Q61H、NRAS−Q61E、NRAS−Q61L、又はNRAS−Q61P)を有する、がんに罹患している個体を治療するのに有用であるという発見にある程度基づいている。
本明細書で提供されるものは、疾患又は障害(例えば、細胞増殖性疾患(例えば、がん(例えば、結腸直腸がん、卵巣がん、肺がん、膵臓がん、及び皮膚がん(例えば、メラノーマ)))を有する個体又は患者からの試料におけるバイオマーカー(例えば、KRAS活性化変異(例えば、KRAS−G12D、KRAS−G12C、KRAS−G12V、KRAS−G13D、KRAS−G12A、KRAS−G12R、KRAS−G12S、KRAS−G13C、KRAS−G13A、KRAS−G13R、KRAS−G13S、KRAS−G13V、KRAS−Q61H、KRAS−Q61K、KRAS−Q61E、KRAS−Q61L、KRAS−Q61P、又はKRAS−Q61R変異)又はNRAS活性化変異(例えば、NRAS−Q61R、NRAS−Q61K、NRAS−G12D、NRAS−G13D、NRAS−G12S、NRAS−G12C、NRAS−G12V、NRAS−G12A、NRAS−G12R、NRAS−G13C、NRAS−G13A、NRAS−G13R、NRAS−G13S、NRAS−G13V、NRAS−Q61H、NRAS−Q61E、NRAS−Q61L、又はNRAS−Q61P))の存在を決定するための、一又は複数の試薬(例えば、ポリペプチド又はポリヌクレオチド)を含むキットである。
In Vitro法
細胞株及び試薬
抗BRAF(sc−5284)及び抗CRAF(sc−133)抗体をSanta Cruz Biotechnologyから購入した。抗MEK1(610122)及び抗CRAF(610152)抗体をBD Biosciencesから購入した。抗pMEK(S217/S221)(9121)、抗ERK(9107)、抗pERK(T202/Y204)(9101)、抗pCRAF(S338)(9427)、抗pEGFR(Y1068)(3777)、AKT(9272)、pAKT(T308)(13038)、切断PARP(9521)、及び抗β−アクチン(4970)をCell Signaling Technologyから購入した。IRコンジュゲート二次抗体ヤギ抗マウス680LT(926−68020)、ヤギ抗ヒト680LT(926− 68032)、及びヤギ抗ウサギ800CW(926−32211)をLi−Corから購入した。二本鎖IRコンジュゲート二次抗体を使用して、Li−Cor CLXで全てのウェスタンブロットをスキャンした。全ての細胞株をAmerican Type Culture Collection(ATCC)から入手し、推奨される培地で維持し、10%加熱不活性化FBS(HyClone、SH3007003HI)、1X GlutaMAX(Gibco、35050−061)、及び1X Pen Strep(Gibco、15140−122)を補充した。A549 shCRAF及びHCT116 shCRAF細胞株をGenentechで生成した。
HCT116結腸がん細胞株をATCC(American Type Culture Collection, Manassas, VA)から購入した。10%ウシ胎児血清を含有するRPMI 1640中でHCT116細胞を培養した。ヘアピンオリゴヌクレオチド(ルシフェラーゼshRNA:センス:5’−GAT CCC CCT TAC GCT GAG TAC TTC GAT TCA AGA GAT CGA AGT ACT CAG CGT AAG TTT TTT GGA AA−3’(配列番号:1)、アンチセンス:5’−AGC TTT TCC AAA AAA CTT ACG CTG AGT ACT TCG ATC TCT TGA ATC GAA GTA CTC AGC GTA AGG GG−3’(配列番号2)及びCRAF shRNA:センス:5’−GAT CCC CGA CAT GAA ATC CAA CAA TAT TCA AGA GAT ATT GTT GGA TTT CAT GTC TTT TTT GGA AA−3’(配列番号3)、アンチセンス:5’−AGC TTT TCC AAA AAA GAC ATG AAA TCC AAC AAT ATC TCT TGA ATA TTG TTG GAT TTC ATG TCG GG−3’(配列番号4)で、ルシフェラーゼ及びCRAF shRNAを安定して発現させるHCT116細胞を作製した。先述の方法(Gray et al. BMC Biotechnol.7:61, 2007; Jaiswal et al. PLoS One.4: e5717, 2009)に基づき、リポフェクタミン(Invitrogen, Carlsbad, CA)を使用してHEK293T細胞中水疱性口内炎ウイルス(VSV−G)エンベロープ糖たんぱく質及びHIV−1パッケージングタンパク質(GAG−POL)を発現させるプラスミドと、ルシフェラーゼ又はCRAF shRNAのいずれかを含有するpHUSH−レンチ−ピューロコンストラクトを、コトランスフェクトすることにより、誘導shRNA含有レンチウイルスコンストラクトを作製した。標的細胞にこれらのウイルスを導入し、ピューロマイシンで選択した。先述のとおり、500ng/mlのドキシサイクリン(Clontech, CA)を含有する培地を使用して、ウェスタンブロット法とその後のshRNAの導入により、細胞をノックダウンについて評価した(Jaiswal et al. PLoS One.4: e5717, 2009)。
RAS変異体、BRAF変異体細胞スクリーニング
4日後に70〜80%の集密を得るように各細胞株について播種密度を最適化した。細胞を384ウェルプレート(Griener、781091)に入れ、翌日、0.1%の最終DMSO濃度で化合物で処理した。CellTiter−Glo(Promega、G7573)を使用して、発光により生細胞の相対数を測定した。GraphPad Prism 6で4パラメーターフィットを使用して生存率曲線を生成した。
9点用量反応で配列決定された480の化合物を含む化合物ライブラリを、A549細胞中のAZ−628又はDMSOのいずれかの固定用量の不存在下又は存在下でスクリーニングした。A549細胞を384ウェルプレートに播種し、24時間後に化合物を添加した。化合物添加の12時間後に細胞生存率を決定した(CellTiter Glo)。曲線を適合させ、IC50生存率と平均生存率の療法の指標を計算した。IC50は、未処理のウェルと比較して阻害が50%である用量である。平均生存率は、各試験用量での適合された生存率の平均である。平均生存率は、試験用量の総数で割った
対数用量/生存率曲線下面積に等しい。全てのデータは、Genedata Screener(GDS)ソフトウェアを使用して適合した。組み合わせ指標は、各化合物についてのAZ−628治療群とDMSO治療群との間の平均生存率における差異である。
3倍希釈を使用して9点用量反応で化合物をスクリーニングした。化合物添加の24時間前に、細胞を384ウェルプレートに播種した。その後、生存率のアッセイ前に、細胞を化合物で72時間又は120時間インキュベートした(CellTiter−Glo、Promega)。アッセイは生物学的に三重で実施した。アッセイを通して、RPMI−1640、2.5% FBS(72時間アッセイ)又は5% FBS(120時間アッセイ)、及び2mM グルタミン中で細胞をインキュベートした(37℃、5% CO2)。報告されたIC50及び平均生存率の指標は、以下の通りである:IC50は、未処理のウェル(すなわち、絶対IC50)と比較して推定された阻害が50%である用量である。平均生存率は、試験用量の総数で割った
対数用量/生存率曲線下面積に等しい。
96ウェル当たり20,000細胞の密度で細胞をプレートに入れ、翌日、0.2% DMSOの最終濃度で2時間化合物で処理した。2時間後、製造業者のプロトコール(Meso Scale Discovery、K15129D)に従って細胞を溶解させ、溶解物をBSAブロックプレートに添加し、4℃で一晩おいた。翌日、アッセイプレートをTBSTで三度洗浄し、検出抗体をRTで1時間添加した。その後、プレートをTBSTで三度洗浄した。1Xリードバッファーをプレートに添加し、Meso Scale Discovery SECTOR Imager 6000ですぐに読み取った。GraphPad Prism 6を使用して、曲線を生成した。
組み合わせの相乗効果の研究のため、細胞を384ウェルプレート(Corning)に入れ、単独で又は組み合わせて様々な濃度の化合物で72時間にわたって処理した。CellTiter−Glo Luminescent Cell Viability Assay(Promega、G7573)を使用して、細胞生存率を決定した。Bliss独立分析法を使用して相乗効果を決定した(Greco et al. Pharmacol. Rev.47: 331-385, 1995; Chou and Talalay. Adv. Enzyme Regul. 22:27-55, 1984; Chou. Cancer Res. 70: 440-446, 2010; Bliss. Ann. Appl. Biol. 25: 31, 1939)。
細胞を一晩播種し、AZ−628及びコビメチニブで、単独で(0.1μM)又は組み合わせて(それぞれ0.1μM)、6時間にわたって処理した。コントロール細胞をDMSO(0.2%最終濃度)で処理した。オンカラムDNAse消化を備えたRNEasyミニキットを使用して、製造業者のプロトコールにより、全RNAを抽出した(Qiagen #74106及び#79254)。試料の品質管理を、RNA−seqによる処理の前にRNAの量及び質を決定するために行った。NanoDrop 8000(Thermo Scientific)を使用してRNA試料の濃度を決定し、Fragment Analyzer(Advanced Analytical Technologies)でRNAの完全性を決定した。TruSeq RNA Sample Preparation Kit v2(Illumina)を使用して、ライブラリ調製のためのインプット材料として0.5μgの全RNAを使用した。2200 TapeStation及びHigh Sensitivity D1000スクリーニングテープ(Agilent Technologies)を使用してライブラリのサイズを確認し、Library quantification kit(KAPA)を使用して、qPCRに基づく方法でそれらの濃度を決定した。ライブラリを多重化し、その後、Illumina HiSeq2500(Illumina)で配列決定して、30Mのシングルエンド50塩基対読み取りを生成した。
細胞を10,000細胞/ウェルで6ウェルプレートに複製して播種し、一晩付着させ、示した化合物で8日間処理した。適切な化合物を含む培地を72時間ごとに補充した。第8日に細胞をPBSで一度流し、固定し、クリスタルバイオレット溶液(Sigma Aldrich、HT90132)で20分間染色し、水で洗浄した。
溶解バッファー(0.5% NP40、20mM Tris、pH7.5、137mM NaCl、10% グリセロール、1mM EDTA)で溶解した細胞+プロテアーゼ阻害剤混合物−complete mini(Roche Applied Science、11836170001)及びホスファターゼ阻害剤混合物(Thermo、78426)。溶解物を10分間15,000rpmで遠心分離し、BCA(Thermo、23227)を使用してタンパク質濃度を決定した。等量のタンパク質をSDS−PAGE NuPAGE 4−12% Bis−Tris Gel(Novex、WG−1403)に供し、ニトロセルロース膜(BioRad、170 - 4159)に移した。ブロッキングバッファー(Li−Cor、927−40000)中でブロック後、示された一次抗体で膜をインキュベートし、二次抗体IRDye 680LT Goat 抗マウス IgG(H + L)(Li−Cor、926−68050)又はIRDye 800CW ヤギ抗ウサギ IgG(H + L)(Li−Cor、926−32211)のいずれかを添加することにより分析した。LiCor Odyssey CLx Scannerで膜を可視化した。
免疫ブロット法に記載の通りに細胞を播種及び溶解した。細胞溶解物を抗CRAF抗体(Millipore 07−396)又は抗BRAF抗体(Millipore 07−453)及び50μlのプロテインAアガロースビーズ(Millipore 16−125)で2時間にわたって4℃でインキュベートした。溶解バッファー+プロテアーゼ及びホスファターゼ阻害剤混合物で洗浄後、40μlのキナーゼバッファー(20mM MOPS、pH7.2、25mM β−グリセロールホスフェート、5mM EGTA、1mM オルトバナジウム酸ナトリウム、1mM DTT、120μM ATP、18mM MgCl2)中、0.4μgの不活性MEK1(Millipore 14−420)で、30℃で30分間プロテインAビーズをインキュベートした。その後試料をウェスタンブロットにより分析した。
GST−Raf−RBDプルダウンアッセイにより、活性GTP負荷Rasのレベルを決定した(Thermo Scientific、16117)。簡潔には、GST−Raf−RBD融合タンパク質をグルタチオンビーズでインキュベートし、製造業者により推奨されるように溶解バッファー中で細胞を収集した。細胞溶解物をGST−Raf−RBD固定化ビーズで4℃で1.5時間インキュベートした。結合したタンパク質をSDSサンプルバッファーで溶出し、ウェスタンブロットにより分析した。
製造業者の指示に従って、リポフェクタミンRNAiMAX試薬(Life Technologies)の存在下で、細胞に20nM siKRAS(L−005069−00−0020)又はsiNTC(D−001810−10−20)(Dharmacon On−TARGETplus(登録商標)プール)を逆トランスフェクトした。培地をトランスフェクションの翌日に変更し、ノックダウン効率を第4日に評価した。
腫瘍タンパク質及びRNA単離
GEMモデル腫瘍試料を収集し、RNALater(Qiagen, Valencia, CA)に貯蔵した。全部のRNAを、製造者の指示に従ってRNeasy Plus Mini kit(Qiagen)を用いて抽出した。Nanodrop(Thermo Scientific, Waltham, MA)を用いてRNAの量を決定した。
製造元の推奨に従ってFluidigm機器又は標準RT−PCRアッセイを使用して、転写読み取り値を評価した。製造業者のプロトコールに従って、Applied Biosystems High Capacity cDNA RT Kit及びTaqMan PreAmp Master Mixを使用して、RNA(100ng)をcDNA合成/前増幅反応させた(Life Technologies, Carlsbad, CA)。増幅後、試料をTEで1から4に希釈し、製造業者のプロトコールに従って、BIOMARKTM HDシステムを使用してFluidigm 96.96 Dynamic ArraysでqPCRを実施した。サイクルしきい値(Ct)を、各標的遺伝子の平均から3つの参照遺伝子の平均を減算し、続いて平均試料dCtから平均ビヒクルdCtを減算することにより、相対発現値(2^−ddCt))の倍数変化に変換した。
タンパク質溶解物を調製するために、細胞を氷冷PBSで一度洗浄し、プロテアーゼ阻害剤錠剤(Roche)及びホスファターゼ阻害剤(Sigma)を補充した1X Cell Extraction Buffer(Invitrogen)に溶解した。BCA Protein Assay(Pierce)を使用して、タンパク質濃度を決定した。1X MOPSランニングバッファー(Invitrogen)中10%Bis−Trisゲルで等量のタンパク質を分離し、ニトロセルロース膜(Invitrogen)に移した。以下のタンパク質に対する抗体を使用した:CRAF、p−ERK、ERK1/2、p−MEK−1/2、MEK−1/2、切断PARP(Cell Signaling)、p−p90RSK、GAPDH(EMD Millipore)、p90RSK(Invitrogen)。増強した化学発光検出試薬(Pierce)を使用して、HRP−コンジュゲートヤギ抗ウサギ抗体及びヤギ抗マウス抗体(Jackson ImmunoResearch)で、又はOdyssey Infrared Imaging System(LI-COR Biosciences)を使用して、IRDye 800コンジュゲート、アフィニティ精製抗ウサギ IgG(LI-COR Biosciences)及びAlexa Fluor 680ヤギ抗マウス IgG(Life Technologies)二次抗体で、抗原抗体相互作用を検出した。
先述の通りに全腫瘍異種移植片モデルの形成及びモニタリングを実施し、これは、Hoeflich et al. Cancer Res.72(1): 210-219, 2012に記載されている。
コビメチニブ(GDC−0973)を、メチルセルロースツイーン(MCT)中で様々な濃度の懸濁液として、Genentechで調製した。AZ−628及びLY3009120をGenentechで合成し、MCTナノ懸濁液として調製した。コビメチニブ、AZ−628、LY3009120、及びビヒクルコントロール投与溶液を、一週間に一度、三週にわたって調製した。製剤は、投薬前に、ボルテックスによりよく混合した。試験物は、温度を4℃〜7℃に維持するように設定された冷蔵庫に貯蔵した。
Hoeflich et al.(Cancer Res. 72(1): 210-219, 2012)に記載されている通りに異種移植の研究を行った。簡潔には、5×106 HCT116細胞又は107 NCI−H2122細胞のいずれかを、平均24−26gの重量のTaconic(Cambridge City, IN)から得たメスのNCRヌードマウス(6−8週齢)の右脇腹に皮下移植した。Genentechで標準的なげっ歯類マイクロ−アイソレータケージにマウスを収容し、腫瘍細胞の移植の前に少なくとも3日間研究条件に順応させた。健康に見え、明白な異常がない動物のみを各試験に使用した。式(L×W×W)/2を用いてデジタルノギス(Fred V. Fowler Company, Inc.)を使用して腫瘍体積を決定した。腫瘍増殖阻害(%TGI)を、%TGI=100×[1−(AUC治療/日)/(AUCビヒクル/日)]であるように、ビヒクルに対する1日当たりのそれぞれの用量群について、近似曲線下面積(AUC)のパーセンテージとして算出した。R v2.12.0のRパッケージnlme、バージョン3.1-97(Pinheiro et al. R Package Version 3. 1-89, 2008)を使用する線形混合効果モデルを使用して、Log2変換された個々の腫瘍体積データに曲線適合を適用した。標準スケールを使用して一週間に二度マウスを計量した。
RAFキナーゼ阻害剤がKRAS変異細胞株において治療的に使用することができるかを決定するために、1.5型RAF阻害剤、ダブラフェニブ、ベムラフェニブ、及び「パラドックスブレーカー」PLX−8394、並びにII型RAF阻害剤、AZ−628及びLY3009120を有するBRAF−V600E細胞株に対して、KRAS変異におけるRAF阻害剤のパネルで細胞生存率を評価した。臨床的に承認された1.5型BRAF阻害剤、ベムラフェニブ及びダブラフェニブ、並びにPLX−8394は、BRAF−V600E変異細胞株で活性を示した(黒で示す)が、KRAS変異細胞株では活性を示さなかった(赤で示す)(図1A)。予測通り、1.5型阻害剤ベムラフェニブ及びダブラフェニブ(PLX−8394は除く)は、KRAS変異腫瘍における下流のpMEKの逆説的な活性化をもたらした(図1B)。1.5型阻害剤とは対照的に、II型汎RAF阻害剤はKRAS変異細胞株のより良好な阻害を示したが、KRAS変異細胞株におけるそれらの力価はBRAF−V600E変異体バックグラウンドで観察される活性よりも弱かった(図1A)。この活性と一致して、II型RAF阻害剤、並びに最近報告されたパラドックスブレーカーPLX−8394は、逆説的な活性化を誘導しない(図1B)。これらの結果を拡大するために、次に三つのII型RAF阻害剤(LY−3009120、MNL−2480及びAZ−628)及びPLX−8394を、161の肺、皮膚、及び結腸細胞株のパネルでスクリーニングした(図1C)。BRAF/RAS野生型細胞株と比較して、RAS変異株におけるこれらの阻害剤の活性の増加は軽度であったが、BRAF−V600細胞株は最も感受性であった(図1C)。これらのデータは、逆説的な活性化の欠如はRAS変異体バックグラウンドにおける感受性の前兆となるのには不十分であること、及びRAFキナーゼ活性は変異体KRAS媒介成長には不可欠ではない場合があることを示唆している。
スクリーニングで最もヒットしたものはMEK阻害剤であったが、全てのMEK阻害剤が同等に相乗的というわけではなかった。コビメチニブ、ピマセルチブ、レファメチニブ、及びPD901は試験された化合物の中で最も高いスコアを示したが、トラメチニブ及びGDC−0623は、どちらも強力なMEK阻害剤ではあるが、平均生存率において差異を示さなかった(図1E)。MEK阻害剤は、不活性RAF−MEK複合体を捕捉する能力に応じて異なる作用機序を有することが以前報告されていた(Hatzivassiliou et al., Nature501:232-236 (2013))。この薬剤安定化複合体は、RAFがMEKをリン酸化するのを妨げる。MEK阻害剤の作用機序がAZ−628との相乗効果に影響を及ぼすかを決定するために、異なる分子機構を有する複数のMEK阻害剤を試験し、不活性RAF−MEK複合体を捕捉し、pMEK を誘導しないMEK阻害剤(例えば、トラメチニブ、GDC−0623、G−573、及びCH−6766)(図1F)は、総量Blissマトリックス分析においてAZ−628との相乗効果も低いことを発見した(図1G)。
in vitroで観察された組み合わせ効果がin vivo有効性に翻訳されたかを決定するために、II型汎RAF阻害剤LY3009120及びAZ−628をNCI−H2122肺(AZ−628+GDC−0973)及びHCT116結腸(LY3009120+GDC−0973)異種移植腫瘍モデル中でコビメチニブと組み合わせて試験した。in vitroデータと一致して、in vivoデータは、それぞれの分子単独の有効性と比較したときに、II型RAF阻害剤+MEK阻害剤の強固な組み合わせ効果を示す(図3A)。単剤としてのLY3009120又はコビメチニブは腫瘍増殖をやや阻害したが、組み合わせると腫瘍を効果的に退縮させることができた。重要なことに、その組み合わせはマウスで良好な態様性を示し、治療後の体重にほとんど変化をもたらさなかったか、又は最小限の変化をもたらした(図3B)。組み合わせがMAPKシグナル伝達にどのように良好に影響したかを評価するために、腫瘍試料を様々な時点で治療の4日後に収集した。MAPK経路シグナル伝達の定量化は、pERK及びpRSKのより良好な抑制をもたらし、試験された全ての時点で、LY3009120とGDC−0973の組み合わせは、いずれかの阻害剤単独の場合と比較して、下流MAPK標的遺伝子、DUSP6及びSPRY4のより深い抑制をもたらすことを実証した(図3C)。血漿及び腫瘍薬物濃度は、阻害活性の改善は薬物曝露の増加には起因しないが、薬物−薬物相互作用に起因することを裏付けた(図3D)。まとめると、RAF及びMEK阻害の組み合わせは、in vivoで有意な組み合わせの有効性を示した。
コビメチニブとII型RAF阻害剤 AZ−628との間で観察される相乗効果の機序を研究するために、KRAS変異及び野生型細胞株のパネルをコビメチニブで24時間処理し、MAPK経路シグナル伝達に対する効果を調査した。コビメチニブで処理した後、KRAS変異細胞においてpMEKレベルの増加を観察したが、KRAS野生型細胞においては観察しなかった、これは、MAPK経路を通じたフラックスの増加を示す(図4A)。KRAS変異及び野生型結腸及び肺がん細胞株のパネルをコビメチニブで24時間処理した後にpMEKの誘導について調査した別個の実験のセットにおいて、KRAS変異及び野生型相乗的細胞ではpMEKレベルの増加を観察したが、KRAS変異及び野生型非相乗的細胞では観察しなかった(図4B−4D)。コビメチニブ処理が経路をどのように変更するかをさらに理解するために、CRAFの免疫沈降を通じてRAF二量体化を評価した。コビメチニブで処理したKRAS変異細胞株(A549、H2122、及びHCT116)では、BRAFはCRAFと強力に共免疫沈降した(図4A)。これは、試験されたKRAS野生型(293T)又はBRAFV600E(A375)細胞株では観察しなかった。続いて、MEK及びATPの外因的な添加を通じてin vitroのキナーゼ活性についてRAF二量体をアッセイした。これらの結果は、KRAS変異細胞株に存在するRAF二量体は、コビメチニブの添加時に非常に活性であり(図4A)、DMSOコントロールで処理したものよりも有意に高いレベルでMEKをリン酸化することができることを示す。この機序をさらに調査するために、KRAS変異及び野生型細胞株中GDC−0973での処理時のRAS−GTPレベルを評価した。KRAS変異株は、ベースラインで及びコビメチニブでの処理時にRAS−GTPレベルの上昇を示し、RAF二量体及びRAFキナーゼ活性の誘導を説明している可能性が高い(図4A)。BRAF−CRAFヘテロ二量体の形成と、ヘテロ二量体のキナーゼ活性の増加はどちらも、50−100nMで起こるコビメチニブの添加に用量依存的であった(図4E)。この結果は、50−100nMの濃度のコビメチニブ及び100nMの濃度のAZ−628が単独では細胞増殖にほとんど影響を与えなかった8日間のクローン原性アッセイにおいて観察された相乗効果を説明する(図2F)。
特定の遺伝子型がII型汎RAF阻害剤とMEK阻害剤の組み合わせに対してより感受性であるかを決定するために、RAS変異が有意であり、頻繁にみられる細胞株(膵臓、肺、結腸直腸、皮膚、卵巣及び血液)を含む、322の細胞株を、AZ−628(20μMで開始)及びコビメチニブ(1μMで開始)の両方の単剤、並びに両化合物の共希釈でスクリーニングした。これらのデータから、相乗効果の尺度として共希釈系列の正のBliss超過を計算した。BRAF−V600変異又は野生型(非RAS/BRAF−V600変異)細胞株と比較して、KRAS及びNRAS変異細胞株において、有意に高い相乗効果スコアを観察した(図5A)(p<0.001、両側t検定)。その後、混合モデル化アプローチを使用して、各組織型からの細胞株を以下のカテゴリーにグループ化した:相乗効果なし、低度の相乗効果、中程度の相乗効果、又は高度の相乗効果。すべての兆候にわたってこれらのカテゴリーの分布を調査したところ、野生型又はBRAF−V600細胞株と比較して、RAS変異体グループにおいて中程度及び高度の相乗効果レスポンダー間の強い関連を観察した(図5A)。
上記のデータは、MEKキナーゼ阻害誘導フィードバックを強く示唆しており、これはKRAS−G13D変異腫瘍で特に強力である。これらの結果を考慮して、AZ−628と430の異なる小分子阻害剤のライブラリの組み合わせを有するA549細胞がスクリーニングされた当初の化合物スクリーニングを再調査した。スクリーニングで最もヒットした中でも汎PI3K阻害剤、ピクチリシブの存在が顕著であった。A549細胞はPIK3CA野生型であるため、この文脈での野生型PI3K阻害は、負のフィードバックループの阻害及びその後のRAFの活性化を通じて、RAS活性化を促進させることができるという仮説を立てた。これをより広く調査するために、213の細胞株のパネルをAZ−628とピクチリシブの組み合わせでスクリーニングした(図7A)。興味深いことに、RAS/RAF変異状態とは無関係のコビメチニブ/ピクチリシブの組み合わせと比較して、AZ−628/ピクチリシブの組み合わせにおいて、相乗効果の大きな全面的な増加を観察した。次に、A549細胞及びHCT116細胞をPI3K阻害剤のパネルで処理し、pMEKレベルを治療後に調査した。試験したPI3K阻害剤の全ては、A549(KRAS−G12S)細胞とHCT116(KRAS−G13D/PIK3CA−H1047R)細胞の両方でpMEKを増加させることがわかったが(図7B及び7C)、ピクチリシブ及びタセリシブはより低い濃度で増加させる。これは、PI3Kの阻害後のMAPK経路を通じたフラックスの増加がPI3K変異状態とは無関係であることを示唆する。この増大したフラックスは、pERK及びpRSKレベルの増加により証明されるように、大きな下流シグナル伝達につがなり、PI3K阻害剤ピクチリシブの濃度に対して用量依存的である(図7D)。PI3Kを阻害する効果がRAS依存性の増加及びRAS−GTPレベルの増加につながるかを調査するために、ピクチリシブ又はコビメチニブのいずれかで処理した細胞における活性RAS−GTPについてRAF1−RBDプルダウンを実施した。ピクチリシブは、コビメチニブにより誘導されたものと同様に、RAS−GTPのレベルを(高濃度であっても)増加させることがわかった(図7E)。
RAF阻害剤、特にII型汎RAF二量体阻害剤も他のRAS遺伝子変異に関して有効であるかを調査するために、BRAF−V600E変異及びNRAS/BRAF野生型細胞株と対比して、NRAS変異メラノーマ細胞株におけるRAF阻害剤のパネル中でII型RAF阻害剤、AZ−628、LY−3009120、及びMNL−2480、並びに「パラドックスブレーカー」PLX−8394を用いて細胞生存率を評価した。II型RAF阻害剤、AZ−628及びLY−3009120は、試験したBRAF−V600E変異細胞株と比較して、試験したNRAS変異メラノーマにおいて、平均生存率(図8A)及びIC50により測定した阻害有効性(図8B)に対してほぼ同等の効果を示した。これらの結果は、NRAS活性化変異を有する、メラノーマのような、がんの治療について、II型汎RAF二量体阻害剤、例えばAZ−628及びLY−3009120は、単独で、又はコビメチニブのようなMEK阻害剤とくみあわせて非常に有効であり得たことを示す。AZ−628又はコビメチニブ(GDC−0973)で処理したNRAS変異、BRAF−V600E、及びNRAS/BRAF野生型細胞株の細胞生存率及びIC50を評価する別個の研究により、NRAS変異がんを治療するためのII型汎RAF二量体阻害剤、例えばAZ−628及びLY−3009120の力価をさらに確認した。この結果は、NRAS変異細胞株に対してBRAF−V600E細胞株においてより大きな有効性を示したコビメチニブと比較して、AZ−628が、NRAS変異及びBRAF−V600E変異細胞株において同等の効果を有することを示した(図8C及び8D)。
前述の発明は明確な理解のために例示及び実施例によってある程度詳細に説明されているが、説明及び実施例は、本発明の範囲を限定するものと解釈されるべきではない。本明細書に引用されるすべての特許及び科学文献の開示内容は、その全体が出典明示により本明細書に援用される。
Claims (58)
- 汎RAF二量体阻害剤及びMEK阻害剤を含む治療から利益を受け得るがんを有する個体を同定する方法であって、個体からの試料をKRAS−G13D変異についてスクリーニングすることを含み、試料中のKRAS−G13D変異の存在が、汎RAF二量体阻害剤及びMEK阻害剤を含む治療から利益を受け得る者として個体を同定する、方法。
- がんを有する個体のための治療を選択するための方法であって、個体からの試料をKRAS−G13D変異についてスクリーニングすることを含み、試料中のKRAS−G13D変異の存在が、汎RAF二量体阻害剤及びMEK阻害剤を含む治療から利益を受け得る者として個体を同定する、方法。
- 個体がKRAS−G13D変異を有し、個体に治療的有効量の汎RAF二量体阻害剤及びMEK阻害剤を投与することをさらに含む、請求項1又は2に記載の方法。
- がんを有する個体を治療する方法であって、
(a)KRAS−G13D変異を有すると決定されている個体からの試料をKRAS−G13D変異についてスクリーニングすること;及び
(b)工程(a)で決定されたKRAS−G13D変異の存在に基づき、個体に治療的有効量の汎RAF二量体阻害剤及びMEK阻害剤を投与すること
を含む方法。 - がんを有する個体を治療する方法であって、個体に治療的有効量の汎RAF二量体阻害剤及びMEK阻害剤を投与することを含み、治療前に、個体からの試料がKRAS−G13D変異についてスクリーニングされており、該試料中のKRAS−G13D変異の存在が決定されている、方法。
- スクリーニングが、KRAS遺伝子の全部又は一部を増幅させること及び配列決定することを含む、請求項1から5のいずれか一項に記載の方法。
- KRAS遺伝子の一部が、KRAS遺伝子のエクソン2である、請求項6に記載の方法。
- KRAS遺伝子のエクソン2のコドン13のKRAS c.38G>A ヌクレオチド置換変異が、KRAS−G13D変異を示す、請求項7に記載の方法。
- KRAS−G13D変異を特徴とするがんの治療的処置における使用のための汎RAF二量体阻害剤及びMEK阻害剤を含む組成物。
- KRAS−G13D変異を特徴とするがんの治療的処置のための医薬の調製のための汎RAF二量体阻害剤及びMEK阻害剤を含む組成物の使用。
- 汎RAF二量体阻害剤及びMEK阻害剤を含む治療から利益を受け得るがんを有する個体を同定する方法であって、個体からの試料をNRAS活性化変異についてスクリーニングすることを含み、試料中のNRAS活性化変異の存在が、汎RAF二量体阻害剤及びMEK阻害剤を含む治療から利益を受け得る者として個体を同定する、方法。
- がんを有する個体のための治療を選択するための方法であって、個体からの試料をNRAS活性化変異についてスクリーニングすることを含み、試料中のNRAS活性化変異の存在が、汎RAF二量体阻害剤及びMEK阻害剤を含む治療から利益を受け得る者として個体を同定する、方法。
- 個体がNRAS活性化変異を有し、個体に治療的有効量の汎RAF二量体阻害剤及びMEK阻害剤を投与することをさらに含む、請求項11又は12に記載の方法。
- がんを有する個体を治療する方法であって、
(a)NRAS活性化変異を有すると決定されている個体からの試料をNRAS活性化変異についてスクリーニングすること;及び
(b)工程(a)で決定されたNRAS活性化変異の存在に基づき、個体に治療的有効量の汎RAF二量体阻害剤及びMEK阻害剤を投与すること
を含む方法。 - がんを有する個体を治療する方法であって、個体に治療的有効量の汎RAF二量体阻害剤及びMEK阻害剤を投与することを含み、治療前に、個体からの試料がNRAS活性化変異についてスクリーニングされており、該試料中のNRAS活性化変異の存在が決定されている、方法。
- スクリーニングが、NRAS遺伝子の全部又は一部を増幅させること及び配列決定することを含む、請求項11から15のいずれか一項に記載の方法。
- NRAS活性化変異を特徴とするがんの治療的処置における使用のための汎RAF二量体阻害剤及びMEK阻害剤を含む組成物。
- NRAS活性化変異を特徴とするがんの治療的処置のための医薬の調製のための汎RAF二量体阻害剤及びMEK阻害剤を含む組成物の使用。
- MEK阻害剤が小分子阻害剤である、請求項1から8及び11から16のいずれか一項に記載の方法。
- 小分子阻害剤が、コビメチニブ(GDC−0973)、セルメチニブ(AZD6244)、ピマセルチブ(AS−703026)、PD0325901、レファメチニブ(BAY86−9766)、ビニメチニブ(MEK162)、BI−847325、トラメチニブ、GDC−0623、G−573、及びCH5126766(RO5126766)、又はそれらの薬学的に許容される塩からなる群より選択される、請求項19に記載の方法。
- 小分子阻害剤が、コビメチニブ(GDC−0973)、セルメチニブ(AZD6244)、ピマセルチブ(AS−703026)、PD0325901、レファメチニブ(BAY86−9766)、又はビニメチニブ(MEK162)、又はその薬学的に許容される塩である、請求項20に記載の方法。
- 小分子阻害剤が、コビメチニブ(GDC−0973)又はその薬学的に許容される塩である、請求項21に記載の方法。
- KRAS活性化変異を含むがんを有する個体を治療する方法であって、個体に治療的有効量の汎RAF二量体阻害剤及びPI3K阻害剤を投与することを含む、方法。
- PI3K阻害剤が小分子阻害剤である、請求項23に記載の方法。
- 小分子阻害剤が、ピクチリシブ(GDC−0941)、タセリシブ(GDC−0032)、及びアルペリシブ(BYL719)、又はそれらの薬学的に許容される塩からなる群より選択される、請求項24に記載の方法。
- PI3K阻害剤が汎PI3K阻害剤である、請求項23又は24に記載の方法。
- 汎PI3K阻害剤が、ピクチリシブ(GDC−0941)又はタセリシブ(GDC−0032)、又はその薬学的に許容される塩である、請求項26に記載の方法。
- 個体がBRAF活性化変異を有しない、請求項23から27のいずれか一項に記載の方法。
- 汎RAF二量体阻害剤が、HM95573、LY−3009120、AZ−628、LXH−254、MLN2480、BeiGene−283、RXDX−105、BAL3833、レゴラフェニブ、及びソラフェニブ、又はそれらの薬学的に許容される塩からなる群より選択される、請求項1から8、11から16、及び19から28のいずれか一項に記載の方法。
- 個体に追加の治療剤を投与することをさらに含む、請求項1から8、11から16、及び19から29のいずれか一項に記載の方法。
- 追加の治療剤が、免疫療法剤、細胞傷害性剤、成長阻害剤、放射線療法剤、及び抗血管新生剤からなる群より選択される、請求項30に記載の方法。
- 試料が、組織試料、細胞試料、全血試料、血漿試料、血清試料、又はそれらの組み合わせである、請求項1から8、11から16、19から22、及び29から31のいずれか一項に記載の方法。
- 試料が組織試料である、請求項32に記載の方法。
- 組織試料が腫瘍組織試料である、請求項33に記載の方法。
- 腫瘍組織試料が、ホルマリン固定及びパラフィン包埋(FFPE)試料、保管試料、フレッシュ試料、又は凍結試料である、請求項34に記載の方法。
- がんが、結腸直腸がん、卵巣がん、肺がん、膵臓がん、皮膚がん、腎臓がん、膀胱がん、乳がん、胃癌、食道がん、中皮腫、メラノーマ、頭頸部がん、甲状腺がん、肉腫、前立腺がん、膠芽細胞腫、子宮頸がん、胸腺癌、白血病、リンパ腫、骨髄腫、菌状息肉腫、メルケル細胞がん、及び血液悪性腫瘍からなる群より選択される、請求項1から8、11から16、及び19から35のいずれか一項に記載の方法。
- がんが結腸直腸がんである、請求項36に記載の方法。
- がんが卵巣がんである、請求項36に記載の方法。
- がんが肺がんである、請求項36に記載の方法。
- がんが膵臓がんである、請求項36に記載の方法。
- がんが皮膚がんである、請求項36に記載の方法。
- 個体がヒトである、請求項1から8、11から16、及び19から41のいずれか一項に記載の方法。
- KRAS活性化変異を特徴とするがんの治療的処置における使用のための汎RAF二量体阻害剤及びPI3K阻害剤を含む組成物。
- KRAS活性化変異を特徴とするがんの治療的処置のための医薬の調製のための汎RAF二量体阻害剤及びPI3K阻害剤を含む組成物の使用。
- 汎RAF二量体阻害剤及び汎PI3K阻害剤を含む組成物。
- 汎PI3K阻害剤が、ピクチリシブ(GDC−0941)又はタセリシブ(GDC−0032)、又はその薬学的に許容される塩である、請求項45に記載の組成物。
- 汎RAF二量体阻害剤が、HM95573、LY−3009120、AZ−628、LXH−254、MLN2480、BeiGene−283、RXDX−105、BAL3833、レゴラフェニブ、及びソラフェニブ、又はそれらの薬学的に許容される塩からなる群より選択される、請求項45又は46に記載の組成物。
- HM95573とピクチリシブ(GDC−0941)、LY−3009120とピクチリシブ(GDC−0941)、AZ−628とピクチリシブ(GDC−0941)、LXH−254とピクチリシブ(GDC−0941)、MLN2480とピクチリシブ(GDC−0941)、BeiGene−283とピクチリシブ(GDC−0941)、RXDX−105とピクチリシブ(GDC−0941)、BAL3833とピクチリシブ(GDC−0941)、レゴラフェニブとピクチリシブ(GDC−0941)、ソラフェニブとピクチリシブ(GDC−0941)、HM95573とタセリシブ(GDC−0032)、LY−3009120とタセリシブ(GDC−0032)、AZ−628とタセリシブ(GDC−0032)、LXH−254とタセリシブ(GDC−0032)、MLN2480とタセリシブ(GDC−0032)、BeiGene−283とタセリシブ(GDC−0032)、RXDX−105とタセリシブ(GDC−0032)、BAL3833とタセリシブ(GDC−0032)、レゴラフェニブとタセリシブ(GDC−0032)、及びソラフェニブとタセリシブ(GDC−0032)、又はそれらの薬学的に許容される塩からなる群より選択される組み合わせを含む、請求項45から47のいずれか一項に記載の組成物。
- 請求項45から48のいずれか一項に記載の組成物を含む薬学的組成物。
- がんの治療的処置における使用のための請求項45から48のいずれか一項に記載の組成物。
- がんが、結腸直腸がん、卵巣がん、肺がん、膵臓がん、皮膚がん、腎臓がん、膀胱がん、乳がん、胃癌、食道がん、中皮腫、メラノーマ、頭頸部がん、甲状腺がん、肉腫、前立腺がん、膠芽細胞腫、子宮頸がん、胸腺癌、白血病、リンパ腫、骨髄腫、菌状息肉腫、メルケル細胞がん、及び血液悪性腫瘍からなる群より選択される、請求項50に記載の組成物。
- がんの治療的処置のための医薬の調製のための、請求項45から48のいずれか一項に記載の組成物の使用。
- 汎RAF二量体阻害剤及びMEK阻害剤を含む治療から利益を受け得るがんを有する個体を同定するためのキットであって、
(a)個体からの試料におけるKRAS−G13D変異の存在を決定するための試薬;及び任意で、
(b)汎RAF二量体阻害剤及びMEK阻害剤を含む治療から利益を受け得るがんを有する個体を同定するための試薬を使用するための指示書
を含むキット。 - 試薬が、KRAS遺伝子の全部又は一部の増幅における使用のための第1のオリゴヌクレオチド及び第2のオリゴヌクレオチドを含む、請求項53に記載のキット。
- 汎RAF二量体阻害剤及びMEK阻害剤を含む治療から利益を受け得るがんを有する個体を同定するためのキットであって、
(a)個体からの試料におけるNRAS活性化変異の存在を決定するための試薬;及び任意で、
(b)汎RAF二量体阻害剤及びMEK阻害剤を含む治療から利益を受け得るがんを有する個体を同定するための試薬を使用するための指示書
を含むキット。 - 試薬が、NRAS遺伝子の全部又は一部の増幅における使用のための第1のオリゴヌクレオチド及び第2のオリゴヌクレオチドを含む、請求項55に記載のキット。
- 汎RAF二量体阻害剤及びPI3K阻害剤を含む治療から利益を受け得るがんを有する個体を同定するためのキットであって、
(a)個体からの試料におけるKRAS活性化変異の存在を決定するための試薬;及び任意で、
(b)汎RAF二量体阻害剤及びPI3K阻害剤を含む治療から利益を受け得るがんを有する個体を同定するための試薬を使用するための指示書
を含むキット。 - 試薬が、KRAS遺伝子の全部又は一部の増幅における使用のための第1のオリゴヌクレオチド及び第2のオリゴヌクレオチドを含む、請求項57に記載のキット。
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KR20220110859A (ko) | 2016-03-04 | 2022-08-09 | 다이호야쿠힌고교 가부시키가이샤 | 악성 종양 치료용 제제 및 조성물 |
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WO2021206167A1 (ja) * | 2020-04-10 | 2021-10-14 | 大鵬薬品工業株式会社 | 3,5-二置換ベンゼンアルキニル化合物とmek阻害剤とを用いた癌治療法 |
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CN112889760A (zh) * | 2021-02-28 | 2021-06-04 | 三江县连兴蛇业有限公司 | 一种虫茶生产大棚及虫茶生产方法 |
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CN111373055A (zh) | 2020-07-03 |
AU2018329925A1 (en) | 2020-03-05 |
TW201919707A (zh) | 2019-06-01 |
WO2019051296A1 (en) | 2019-03-14 |
MX2020002553A (es) | 2020-07-22 |
AU2018329925A8 (en) | 2020-03-19 |
EP3679159A1 (en) | 2020-07-15 |
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