JP2020530467A - 癌転移を処置するためにキナーゼを標的とする方法 - Google Patents
癌転移を処置するためにキナーゼを標的とする方法 Download PDFInfo
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Abstract
Description
本発明は、国立衛生研究所によって与えられた補助金番号R01 CA112567およびR01 CA184836の下で政府支援によって成された。政府は本発明において一定の権利を有する。
本発明は、一般に、分子生物学および医学の分野に関する。より具体的には、本発明は、癌、特に脳転移の処置のためにキナーゼを標的とする方法に関する。
脳転移は何百万人の癌患者を冒し、原発性脳腫瘍の10倍を超える。主な腫瘍性疾患(例えば、黒色腫、肺癌、乳癌、および結腸癌)は脳転移の高い発生率を有する。脳転移の診断後の1年生存率は20%未満である。最近になって、標的癌療法の進歩(例えば、トラスツズマブ、T-DMl)が、全身性疾患のよりよい制御を通して患者の生存を延ばした。しかし、患者が後に再発を有する場合、患者は、増加していく割合(例えば30%超)で脳転移を発症し、好結果の標的療法のこの時代において新たな課題を示している。現在の治療選択肢は、脳転移を有する患者については限定的かつ単に対症的である。
第1の態様において、本開示は、癌を有する対象における脳転移を阻害するための方法であって、方法が、有効量のキナーゼ阻害剤を対象へ投与する工程を含み、キナーゼ阻害剤が、ADCK4、BTK、CAMK4、CDK5、CDK5R1、CLK3、LIMK2、PAK4、PMVK、PRKACB、PRKACG、PRKCI、TSSK6、およびZC3HC1からなる群より選択されるキナーゼを標的とする、方法を提供する。いくつかの局面において、対象はヒトである。ある局面において、キナーゼ阻害剤はsiRNAまたはmiRNAである。他の局面において、キナーゼ阻害剤は選択的薬理学的阻害剤である。
キナーゼのドラッガビリティを利用することによる脳転移の処置における使用について脳転移のドライバーキナーゼを同定するために、本研究は、乳癌脳転移を促進し、脳転移の有効な阻害についての治療標的として役立ち得る新規のキナーゼを発見するために、ヒトキノームの無作為のインビボスクリーニングを行った。現在利用可能なキナーゼ標的は、細胞培養皿中において癌細胞増殖を促進することにおけるそれらの役割によって同定されたが、今回同定されたキナーゼは、動物中における脳転移のドライバーを特異的に探す機能的インビボスクリーニングから生じた。従って、本方法によって同定された標的は、特異的に脳転移の成長において役割を果たす。
明細書において使用される場合、「1つの(a)」または「1つの(an)」は1つまたは複数を意味し得る。特許請求の範囲において使用される場合、「含む」という単語と共に使用される場合は、「1つの(a)」または「1つの(an)」という単語は1つまたは1つを超えることを意味し得る。
ある態様において、本開示は、本研究のインビボキナーゼスクリーニングによって転移促進キナーゼ(表1)として同定されたキナーゼの阻害剤を投与することによって、脳転移のような、転移を処置する(例えば、阻害するまたは減少させる)方法を提供する。処置は、転移、特に脳転移の発生を阻害するために、原発腫瘍を有する対象において行われ得る。他の局面において、対象は、脳転移のような、転移性腫瘍と診断され得、処置は、例えば、少なくとも10%、特に20%、30%、40%、50%、60%、70%、80%、90%、95%、98%、99%、または100%、脳転移を減少させる。
サイクリン依存性キナーゼ16(CDK16)とも呼ばれる、セリン/トレオニン-プロテインキナーゼPCTAIRE-1(PCTK1)遺伝子は、小胞媒介輸送プロセスおよびエキソサイトーシスにおいて役割を果たすキナーゼをコードする。それはまた、ニューロン分化および樹状突起発達を調節する。PCTK1は、RNAiおよび/またはPCTK1について選択的な薬理学的阻害剤によって阻害され得る。例えば、本方法において使用され得るPCTK1について選択的な一つの阻害剤は、インディルビンE804またはその類似体である(Hoessel et al., 1999; Cweik et al., 2015;参照により両方とも本明細書に組み入れられる)。阻害剤は、H結合相互作用を介してヒンジ領域と相互作用することによってATP部位へ結合する。PCTK1を阻害するために使用され得る他の阻害剤としては、I型キナーゼ阻害剤、例えば、トリアゾロ-ジアミン化合物Cdk1/2阻害剤III、アルステルパウロン、2-シアノエチル、インディルビンE804およびアミノピリミジニル化合物Cdk2/9阻害剤が挙げられる。CDK2阻害剤、例えば、オキシンドールGW300657XおよびGW416981X、ならびにピラゾロ[1,5-b]ピリダジン化合物GW779439Xもまた、PCTK1の阻害のために使用され得る。
スフィンゴシンキナーゼ(SPHK1)は、細胞増殖および生存を促進し、S1P/セラミドレオスタットを調節する重要な酵素である。SPHKの非アイソザイム特異的阻害剤、例えば、L-スレオ-ジヒドロスフィンゴシン(サフィンゴール)およびN,N-ジメチルスフィンゴシン(DMS)が、本方法において使用され得る。いくつかの局面において、SPHK1は、米国特許第8,372,888号に記載されるようなBML-258、米国特許出願公開第20080167352号に記載されるような3-(4-クロロ-フェニル)-アダマンタン-1-カルボン酸 (ピリジン-4-イルメチル)-アミド、[(2R)-1-[[4-[[3-(ベンゼンスルホニルメチル)-5-メチルフェノキシ]メチル]フェニル]メチル]ピロリジン-2-イル]メタノール(PF-543)、スフィンゴシンキナーゼ阻害剤2 (SKI II; 4-[[4-(4-クロロフェニル)-2-チアゾリル]アミノ]フェノール)、SKI 5C (CAY10621)、N,N-ジメチルスフィンゴシン((2S,3R,4E)-2-(ジメチルアミノ)-4-オクタデセン-1,3-ジオール)、MP A08 (4-メチル-N-[2-[[[2-[[(4-メチルフェニル)スルホニル]アミノ]フェニル]イミノ]メチル]フェニル]ベンゼンスルホンアミド)、SKI 178 (N'-(1-(3,4-ジメトキシフェニル)エチリデン)-3-(4-メトキシフェニル)-1H-ピラゾール-5-カルボヒドラジド)、またはそれらの類似体、誘導体もしくは薬学的に許容される塩によって阻害される。特定の局面において、SPHK1の阻害剤はフィンゴリモド(Gilenya)またはサフィンゴールである。
細胞外シグナル調節キナーゼ6(ERK6)またはストレス活性化プロテインキナーゼ3(SAPK3)としても公知の、マイトジェン活性化プロテインキナーゼ12(MAPキナーゼ12)は、ヒトにおいてMAPK12遺伝子によってコードされる酵素である。マイトジェン活性化プロテインキナーゼファミリーのメンバーの活性化は、細胞外シグナルの伝達のための主要な機構である。ストレス活性化プロテインキナーゼは、MAPキナーゼの1つのサブクラスである。この遺伝子によってコードされるタンパク質は、筋芽細胞から筋管への分化中にシグナル伝達物質として機能する。MAPK12は、SB 203580、ドラマピモド(BIRB 796)、LY2228820、または当技術分野において公知のMAPK12の他の阻害剤によって阻害され得る。
細胞分裂プロテインキナーゼ5は、ヒトにおいてCDK5遺伝子によってコードされる酵素である。CDK5は、脳の適切な発達のために必要とされ、活性化されるために、CDK5はCDK5R1またはCDK5R2と会合しなければならない。CDK5またはCDK5R1は、ディナシクリブ(SCH727965)、ビス-インドールインディルビン、(S)-CR8、ケンパウロン、PHA-793887、AT7519、ロスコビチン(セリシクリブ、CYC202)、ミルシクリブ(PHA-848125)、SNS-032(BMS-387032)、またはオロモウシンによって、本方法において阻害され得る。特定の局面において、CDK5の阻害剤はCYC-065またはDCAM-422である。
LIMキナーゼ2(LIMK2)はアクチン細胞骨格の調節因子である。LIMK2は、アクチン脱重合因子(ADF)ファミリーのメンバーである、コフィリンをリン酸化し、従って不活性化する。LIMK2の例示的な阻害剤としては、BMS-5(CAS No. 1338247-35-0)、Pyr-1(LIMNIB)、ダムナカンタール、Par-3、T56-LIMKi、およびLX7101が挙げられるが、これらに限定されない。LX7101は、眼内圧の調節に関連するキナーゼである、LIMドメインキナーゼ2(LIMK2)の、ピロロピリミジン系の局所送達される阻害剤である。
コエンザイムQ8B(COQ8B)またはAarFドメイン含有プロテインキナーゼ4(ADCK4)は、好気性細胞呼吸についての脂溶性電子輸送体である。ADCK4は、当技術分野において公知のRNAiまたは阻害剤によって阻害され得る。
チロシン-プロテインキナーゼBTKとしても公知のブルトンチロシンキナーゼ(BtkまたはBTK)は、ヒトにおいてBTK遺伝子によってコードされる酵素である。BTKは、B細胞発生において役割を果たすキナーゼである。B細胞受容体(BCR)および肥満細胞上のFCER1の結合によって活性化されるシグナル伝達経路におけるBTKの機能は、十分に確立されている。ヒトにおけるBTKの機能的突然変異は、プロ-およびプレ-B細胞段階間での遮断を伴うB細胞発生の欠陥によって特徴付けられる原発性免疫不全症をもたらす。BTKの例示的な阻害剤としては、イブルチニブ(PCI-32765)、アカラブルチニブ、ONO-4059、スペブルチニブ(AVL-292、CC-292)、BGB-3111、およびHM71224が挙げられるが、これらに限定されない。
カルシウム/カルモジュリン依存性プロテインキナーゼIV型は、ヒトにおいてCAMK4遺伝子によってコードされる酵素である。この遺伝子の産物は、セリン/トレオニンプロテインキナーゼファミリー、およびCa2+/カルモジュリン依存性プロテインキナーゼサブファミリーに属する。この酵素は、リンパ球、ニューロンおよび雄性生殖細胞における転写調節に関与している限定的な組織分布を伴う多機能性セリン/トレオニンプロテインキナーゼである。CAMK4の例示的な阻害剤は、KN-93 (N-[2-[[[3-(4-クロロフェニル)-2-プロペニル]メチルアミノ]メチル]フェニル]-N-(2-ヒドロキシエチル)-4-メトキシベンゼンスルホンアミド)である。
CDC様キナーゼ3(CLK3)は、スプライシング因子のセリン/アルギニンリッチ(SR)ファミリーの核内分布を調節する核二重特異性キナーゼである。CLK3の例示的な阻害剤はKH-CB19である。使用され得る他の阻害剤としては、R547、A-674563、NVP-TAE684、およびAT-7519が挙げられる。
トリオキナーゼ/FMNシクラーゼまたはジヒドロキシアセトンキナーゼ2ホモログ(DAK)は、ヒトにおいてDAK遺伝子によってコードされる酵素である。DAKは、ジヒドロキシアセトンをリン酸化し、さらに、FADからのリボフラビン4',5'-ホスフェート(akaサイクリンFMN)の形成を触媒する。DAKは、当技術分野において公知のRNAiまたは阻害剤によって阻害され得る。
MAPキナーゼ7およびERK5としても公知のマイトジェン活性化プロテインキナーゼ7は、MAPキナーゼファミリーのメンバーである。MAPキナーゼは、複数の生化学的シグナルについての統合点として作用し、増殖、分化、転写調節および発生のような多種多様の細胞プロセスに関与する。このキナーゼは、マイトジェン活性化プロテインキナーゼキナーゼ5(MAP2K5/MEK5)によって特異的に活性化される。それは、受容体チロシンキナーゼおよびGタンパク質共役受容体を含む、様々な受容体分子の下流のシグナル伝達プロセスに関与する。細胞外シグナルに応答して、このキナーゼは細胞核へトランスロケートし、ここで、それは、種々の転写因子をリン酸化し、そして活性化することによって、遺伝子発現を調節する。ERK5の例示的な阻害剤としては、ERK5-IN-1 (11-シクロペンチル-2-[[2-エトキシ-4-[[4-(4-メチル-1-ピペラジニル)-1-ピペリジニル]カルボニル]フェニル]アミノ]-5,11-ジヒドロ-5-メチル-6H-ピリミド[4,5-b][1,4]ベンゾジアゼピン-6-オン)、BIX 02189、XMD17-109、およびXMD 8-92が挙げられるが、これらに限定されない。
Fyn関連キナーゼ(FRK)はプロテインキナーゼのTYRファミリーに属する。このチロシンキナーゼは、核タンパク質であり、細胞周期のG1およびS期中に機能し、増殖を抑制し得る。FRKの例示的な阻害剤としては、チロシンキナーゼ阻害剤、例えば、ダサチニブ、モテサニブ(A1VIG-706)、ドラマピモド(BIRB 796)、ペリチニブ(EKB-569)、ソラフェニブ、バンデタニブ、カネルチニブ(CI-1033)およびイマチニブ(STI-571)が挙げられるが、これらに限定されない。
MAPキナーゼキナーゼ7またはMKK7としても公知の、二重特異性マイトジェン活性化プロテインキナーゼキナーゼ7は、ヒトにおいてMAP2K7遺伝子によってコードされる酵素である。このタンパク質は、マイトジェン活性化プロテインキナーゼキナーゼファミリーのメンバーである。MKK7は、炎症性サイトカイン、および環境ストレスに対する細胞応答を媒介するシグナル伝達に関与する。MAP2K7は、DTP3 ((R)-2-((R)-2-アセトアミド-3-(4-ヒドロキシフェニル)プロパンアミド)-N-((R)-1-アミノ-1-オキソ-3-フェニルプロパン-2-イル)-5-グアニジノペンタンアミドトリフルオロアセテート)によって阻害され得る。
セリン/トレオニン-プロテインキナーゼPAK4は、セリン/トレオニンキナーゼのPAKファミリーの6つのメンバーのうちの1つである。PAK4は、細胞質の細胞内ドメインおよび核に局在化する。PAK4は、細胞骨格リモデリング、表現型シグナル伝達および遺伝子発現を調節し、指向性運動性、浸潤、転移、および増殖に影響を与える。PAK4は、PF-3758309、LCH-7749944、グラウカルビノン、KY-04031、KY-04045、1-フェナントリル-テトラヒドロイソキノリン誘導体、(-)-β-ヒドラスチン、Inka1、GL-1196、GNE-2861、ならびにマイクロRNA、例えば、miR-145、miR-433、およびmiR-126によって阻害され得る。
ホスホメバロン酸キナーゼ(PMVK)はメバロン酸経路中にあり、それは、5-ジホスホメバロン酸への5-ホスホメバロン酸の変換を触媒し、これは、イソプレノイド生合成のメバロン酸経路中の第5段階である。PMVKは、CSDDD_1633 (1,4-ビス((2-((γ1-オキシダニル)ジオキソ-γ6-スルファニル)-4-メチルフェニル)アミノ)-5,8-ジヒドロキシ-4a,9a-ジヒドロアントラセン-9,10-ジオン)、CSDDD_2260 (2,2'-((4-((2-(γ1-オキシダニル)-2-オキソエチル)チオ)-[1,1'-ビフェニル]-2,6-ジイル)ビス(スルファンジイル))ジアセテート、CSDDD_2419 ((E)-4-((2,4-ジヒドロキシフェニル)ジアゼニル)-5-メチルナフタレン-2,7-ジスルホネート)またはルテオリン(参照により本明細書に組み入れられる、Boonsri et al., 2013に記載される)の投与によって阻害され得る。
cAMP依存性プロテインキナーゼ触媒サブユニットベータ(PRKACB)は、様々な細胞機能についてのシグナル伝達分子である。cAMPは、種々の標的タンパク質のリン酸化を通してシグナルを伝達する、プロテインキナーゼA(PKA)を活性化することによってその効果を発揮する。PKAの不活性ホロ酵素は、2つの調節サブユニットおよび2つの触媒サブユニットから構成される四量体である。cAMPは、4つのcAMPへ結合された調節サブユニットの二量体および2つの遊離単量体触媒サブユニットへの不活性ホロ酵素の解離を引き起こす。AMP依存性プロテインキナーゼ触媒サブユニットガンマ(PRKACG)は、マクロファージ中のCCR5経路およびギャップジャンクション中のシグナリングにおいて役割を果たす。PRKACBまたはPRKACGは、当技術分野において公知のRNAiまたは阻害剤によって阻害され得る。
プロテインキナーゼCイオタ型(PRKCI)およびプロテインキナーゼCデルタ型(PRKCD)は、セリン/トレオニンプロテインキナーゼのプロテインキナーゼC(PKC)ファミリーのメンバーである。PKCファミリーは、少なくとも8つのメンバーを含み、これらは差次的に発現され、多種多様の細胞プロセスに関与する。このプロテインキナーゼは、カルシウム非依存性かつリン脂質依存性である。それは、ホルボールエステルまたはジアシルグリセロールによって活性化されない。このキナーゼは小さなGTPアーゼRAB2との直接的相互作用によって小胞小管クラスター(VTC)へ動員され得、ここで、このキナーゼはグリセルアルデヒド-3-リン酸脱水素酵素(GAPD/GAPDH)をリン酸化し、初期分泌経路中の微小管動態において役割を果たす。このキナーゼは、薬物誘発アポトーシスに対するBCL-ABL媒介耐性のために必要であることがわかり、従って、薬物誘発アポトーシスから白血病細胞を保護する。これらのキナーゼについての例示的な阻害剤としては、プロテインキナーゼ阻害剤、例えば、ビスインドリルマレイミドII、カルホスチンC、ジヒドロスフィンゴシン、およびLY 333531塩酸塩が挙げられるが、これらに限定されない。具体的な局面において、PRKCIの阻害剤はリドーラ(オーラノフィン)またはRXDX-108である。
精巣特異的セリンキナーゼ6(TSSK6)。コードされるキナーゼは、広い発現パターンを有するが、生殖能力に対する効果に起因して精巣特異的と記載される。TSSK6は、当技術分野において公知のRNAiまたは阻害剤によって阻害され得る。
ウリジン-シチジンキナーゼ2(UCK2)は、それぞれ、ウリジン一リン酸(UMP)およびシチジン一リン酸(CMP)へのウリジンおよびシチジンのリン酸化を触媒する。これは、RNAおよびDNA合成に必要なピリミジンヌクレオシド三リン酸の産生における第1段階である。いくつかの局面において、UCK2の阻害剤はフラボカワインBまたはアルピネチンである(Malami et al., 2016)。
ジンクフィンガーC3HC型タンパク質1(ZC3HC1)としても公知の、ALKの核相互作用パートナー(NIPA)は、核細胞内位置中に排他的に発現されるが、多くの組織および細胞タイプにおいて普遍的に発現される。NIPAは、有糸分裂へのエントリーの調節に関与するskp1カリンF-ボックス(SCF)型ユビキチンE3リガーゼ(SCFNIPA)複合タンパク質である。ZC3HC1は、当技術分野において公知のRNAiまたは阻害剤によって阻害され得る。
いくつかの態様において、キナーゼは、siRNAまたはmiRNAのような、RNA干渉によって阻害され得る。RNAは、siRNA、shRNA、プラスミド、mRNA、miRNA、またはncRNA、特にsiRNAまたはmiRNA治療薬であり得る。miRNAは、miRNA模倣体、またはmiRNA前駆体であり得る。RNAのサイズは、100ヌクレオチド長未満、例えば、75ヌクレオチド長未満、特に50ヌクレオチド長未満であり得る。例えば、RNAは、約10〜100ヌクレオチド、例えば20〜50ヌクレオチド、特に10〜20、15〜25、20〜30、25〜35、30〜40、または45〜50ヌクレオチドの長さを有し得る。
個体における癌の進行、特に癌転移を処置するかまたは遅らせるための方法であって、有効量のキナーゼ阻害剤、例えば、本開示において同定された転移促進キナーゼについての阻害剤(表1)を個体へ投与する工程を含む方法を、本明細書に提供する。本開示のある態様は、転移促進キナーゼの阻害剤の投与を伴う、対象にける疾患を処置または予防する方法に関する。疾患は、対象に影響を与え得る任意の疾患であり得る。特定の態様において、疾患は過剰増殖性疾患である。より特定の態様において、疾患は癌である。
本明細書に記載される方法の一部は、本開示において同定された転移促進キナーゼの阻害剤を含む組成物の薬学的有効量の投与を伴う方法に関する。
製剤化されると、キナーゼ阻害剤は、投薬製剤と適合する様式で、治療的に有効であるような量で、投与される。
キナーゼ阻害剤の薬学的有効量は、意図される目的、例えば、細胞死の阻害に基づいて決定される。処置数および用量の両方に従う、投与される量は、処置される対象、対象の状態、望まれる保護、および投与経路に依存する。治療剤の正確な量はまた、実行者の判断に依存し、各個体に特有である。
本開示のある態様は、疾患の処置または予防のための1つまたは複数の療法の第2形態を提供する。例えば、疾患は、癌などの、過剰増殖性疾患であり得る。
使用され得る化学療法剤の例には、アルキル化剤、例えば、チオテパおよびシクロホスファミド:スルホン酸アルキル、例えば、ブスルファン、インプロスルファン、およびピポスルファン;アジリジン、例えば、ベンゾドーパ、カルボコン、メツレドーパ、およびウレドーパ;アルトレタミン、トリエチレンメラミン、トリエチレンホスフォラミド、トリエチレンチオホスフォラミド、およびトリメチロロメラミンを含む、エチレンイミンおよびメチラメラミン;アセトゲニン(特に、ブラタシンおよびブラタシノン);カンプトテシン(合成アナログトポテカンを含む);ブリオスタチン;カリスタチン;CC-1065(そのアゾゼレシン、カルゼレシンおよびビゼレシン合成アナログを含む);クリプトフィシン(特に、クリプトフィシン1およびクリプトフィシン8);ドラスタチン;デュオカルマイシン(合成アナログ、KW-2189およびCB1-TM1を含む);エリュテロビン;パンクラチスタチン;サルコジクチン;スポンジスタチン;ナイトロジェンマスタード、例えば、クロラムブシル、クロルナファジン、コロホスファミド(cholophosphamide)、エストラムスチン、イフォスファミド、メクロレタミン、メクロレタミンオキシドヒドロクロリド、メルファラン、ノブエンビキン、フェネステリン、プレドニムスチン、トロホスファミド、およびウラシルマスタード;ニトロソウレア、例えば、カルムスチン、クロロゾトシン、フォテムスチン、ロムスチン、ニムスチン、およびラニムヌスチン;抗生剤、例えば、エンジイン抗生剤(例えば、カリチアマイシン、特に、カリチアマイシンガンマlIおよびカリチアマイシンオメガI1);ダイネマイシンAを含む、ダイネマイシン;ビスホスホネート、例えば、クロドロネート;エスペラマイシン;ならびにネオカルチノスタチン発色団および関連する色素タンパク質エンジイン抗生剤発色団、アクラシノマイシン、アクチノマイシン、アウトラマイシン、アザセリン、ブレオマイシン、カクチノマイシン、カラビシン、カルミノマイシン、カルジノフィリン、クロモマイシン、ダクチノマイシン、ダウノルビシン、デトルビシン、6-ジアゾ-5-オキソ-L-ノルロイシン、ドキソルビシン(モルホリノ-ドキソルビシン、シアノモルホリノ-ドキソルビシン、2-ピロリノ-ドキソルビシンおよびデオキシドキソルビシンを含む)、エピルビシン、エソルビシン、イダルビシン、マルセロマイシン、マイトマイシン、例えば、マイトマイシンC、ミコフェノール酸、ノガラマイシン、オリボマイシン、ペプロマイシン、ポトフィロマイシン、ピューロマイシン、クエラマイシン、ロドルビシン、ストレプトニグリン、ストレプトゾシン、ツベルシジン、ウベニメックス、ジノスタチン、およびゾルビシン;抗代謝物質、例えば、メトトレキサートおよび5-フルオロウラシル(5-FU);葉酸アナログ、例えば、デノプテリン、プテロプテリン、およびトリメトレキサート;プリンアナログ、例えば、フルダラビン、6-メルカプトプリン、チアミプリン、およびチオグアニン;ピリミジンアナログ、例えば、アンシタビン、アザシチジン、6-アザウリジン、カルモファー、シタラビン、ジデオキシウリジン、ドキシフルリジン、エノシタビン、およびフロックスウリジン;アンドロゲン、例えば、カルステロン、ドロナノロンプロピオナート(dronanolone propionate)、エピチオスタノール、メピチオスタン、およびテストラクトン;抗副腎薬、例えば、ミトタンおよびトリロスタン;葉酸補充物質、例えば、フロリン酸(frolinic acid);アセグラトン;アルドホスファミドグリコシド;アミノレブリン酸;エニルウラシル;アムサクリン;ベストラブシル;ビサントレン;エダトラキサート;デフォファミン;デメコルシン;ジアジクオン;エルフォルミチン;エリプチニウムアセテート;エポチロン;エトグルシッド;ガリウムニトレート;ヒドロキシ尿素;レンチナン;ロニダイニン;メイタンシノイド、例えば、メイタンシンおよびアンサミトシン;ミトグアゾン;ミトキサトロン;モピダンモール;ニトラエリン;ペントスタチン;フェナメット;ピラルビシン;ロソキサントロン;ポドフィリン酸;2-エチルヒドラジド;プロカルバジン;PSK多糖複合体;ラゾキサン;リゾキシンン;シゾフィラン;スピロゲルマニウム;テヌアゾン酸;トリアジクオン;2,2',2”-トリクロロトリエチルアミン;トリコテセン(特に、T-2毒素、ベラクリンA、ロリジンA、およびアングイジン);ウレタン;ビンデシン;ダカルバジン;マンノムスチン;ミトブロニトール;ミトラクトール;ピポブロマン;ガシトシン;アラビノシド(「Ara-C」);シクロホスファミド;タキソイド、例えば、パクリタキセルおよびドセタキセルゲムシタビン;6-チオグアニン;メルカプトプリン;プラチナ配位錯体、例えば、シスプラチン、オキサリプラチン、およびカルボプラチン;ビンブラスチン;プラチナ;エトポシド(VP-16);イフォスファミド;ミトキサントロン;ビンクリスチン;ビノレルビン;ノバントロン;テニポシド;エダトレキサート;ダウノマイシン;アミノプテリン;ゼロダ;イバンドロナート;イリノテカン(例えば、CPT-11);トポイソメラーゼ阻害剤RFS 2000;ジフルオロメチルオルニチン(DMFO);レチノイド、例えば、レチノイン酸;カペシタビン;カルボプラチン、プロカルバジン、プリコマイシン、ゲムシタビエン、ナベルビン、ファルネシルタンパク質トランスフェラーゼ阻害剤、トランスプラチナ、ならびに上記のいずれかの薬学的に許容される塩、酸、または誘導体が含まれる。
DNA損傷を引き起こし、かつ幅広く用いられている他の因子は、γ線、X線として一般的に知られているもの、および/または腫瘍細胞に対する放射性同位体の指向性送達を含む。DNA損傷因子の他の形態、例えば、マイクロ波、陽子ビーム照射、ならびにUV照射も意図される。これらの因子の全ては、DNAに対して、DNAの前駆体に対して、DNAの複製および修復に対して、ならびに染色体の集合および維持に対して、広範囲の損傷に影響を与える可能性が高い。X線についての線量範囲は、長期間(3〜4週間)についての50〜200レントゲンの1日線量から、2000〜6000レントゲンの単一線量までの範囲にわたる。放射性同位体についての線量範囲は、広く異なり、同位体の半減期、放出された放射線の強度および種類、ならびに新生物細胞による取込みに依存する。
当業者は、免疫療法が、本態様の方法と組み合わせてまたは連動させて用いられ得ることを理解するだろう。癌処置の文脈において、免疫療法は、一般的に、癌細胞を標的とし、それを破壊するために、免疫エフェクター細胞および分子を使用することに依存する。リツキシマブ(RITUXAN(登録商標))は、その一例である。免疫エフェクターは、例えば、腫瘍細胞の表面上にあるいくつかのマーカーに特異的な抗体であり得る。抗体単独を療法のエフェクターとして使用することもでき、または、抗体が、細胞殺傷に実際に作用する他の細胞を動員してもよい。抗体はまた、薬物または毒素(化学療法剤、放射性核種、リシンA鎖、コレラ毒素、百日咳毒素など)にコンジュゲートされ、標的化剤として機能することができる。あるいは、エフェクターは、直接的または間接的に腫瘍細胞標的と相互作用する表面分子を有するリンパ球であり得る。様々なエフェクター細胞は、細胞傷害性T細胞およびNK細胞を含む。
癌を有する人のおよそ60%は、予防的、診断的または病期分類的、治療的、および緩和的手術を含む、ある種の手術を受ける。治療的手術は、癌組織の全てまたは一部が物理的に除去されるか、切除されるか、および/または破壊される切除術を含み、また他の療法、例えば、本態様の処置、化学療法、放射線療法、ホルモン療法、遺伝子療法、免疫療法、および/または代替療法と併用することができる。腫瘍切除術は、腫瘍の少なくとも一部の物理的除去を指す。腫瘍切除術に加えて、手術による処置は、レーザー手術、冷凍外科手術、電気手術、および顕微鏡制御された手術(モース手術)を含む。
処置の治療効果を改善するために本態様の特定の局面と組み合わせて他の剤を用いてもよいことが意図される。これらのさらなる剤には、細胞表面受容体およびGAPジャンクションの上方制御に作用する剤、細胞増殖抑制剤および分化剤、細胞接着の阻害剤、過剰増殖細胞のアポトーシス誘導剤への感受性を増大させる剤、または他の生物学的剤が含まれる。GAPジャンクションの数を高めることによる細胞内シグナリングの増大は、隣接する過剰増殖細胞集団に対する抗過剰増殖効果を増大し得る。他の態様において、細胞増殖抑制剤または分化剤は、処置の抗過剰増殖効果を改善するために本態様の特定の局面と組み合わせて用いることができる。細胞接着の阻害剤は、本態様の効果を改善するために意図される。細胞接着阻害剤の例は、接着斑キナーゼ(FAK)阻害剤およびロバスタチンである。
態様の様々な局面において、治療剤ならびに/または他の治療剤および送達剤を含有するキットが想定される。いくつかの態様において、本態様は、本態様のキナーゼ阻害剤組成物の調製および/または投与のためのキットを意図する。キットは、本態様の薬学的組成物のいずれかを含有する1つまたは複数の密封されたバイアルを含み得る。キットは、例えば、キナーゼ阻害剤、ならびに、本態様の成分を調製、製剤化および/もしくは投与するための、または本発明の方法の1つもしくは複数の工程を行うための試薬を含み得る。いくつかの態様において、キットはまた、好適な容器を含み得、これは、キットの成分と反応しない容器、例えば、エッペンドルフチューブ、アッセイプレート、注射器、ボトル、またはチューブである。容器はプラスチックまたはガラスのような滅菌可能な材料から作られ得る。
以下の実施例は、本発明の好ましい態様を実証するために含まれる。当業者であれば、後に続く実施例において開示された技術は、本発明の実施において十分に機能することが本発明者により見出された技術を示し、従って、その実施のための好ましいモードを構成するものとして考慮することができることを理解するべきである。しかし、当業者であれば、本開示に照らして、開示される特定の態様において多数の変更を加えることができること、そして本発明の精神および範囲から逸脱することなく同様または類似する結果を依然として得ることができることを理解するべきである。
キナーゼ過剰発現スクリーニングを、脳転移の新規のドライバーを特定するためにインビボで行った(図1)。アッセイを、キナーゼが脳転移の成長を増強するかどうかを決定するために行った。スクリーニングされた17のキナーゼプールのうち、14がマウス生存を少なくとも20%減少させた。
Claims (76)
- 癌を有する対象における脳転移を阻害するための方法であって、
該方法が、有効量のキナーゼ阻害剤を対象へ投与する工程を含み、該キナーゼ阻害剤が、ADCK4、BTK、CAMK4、CDK5、CDK5R1、CLK3、LIMK2、PAK4、PMVK、PRKACB、PRKACG、PRKCI、TSSK6、およびZC3HC1からなる群より選択されるキナーゼを標的とする、前記方法。 - 癌が乳癌である、請求項1記載の方法。
- 乳癌がトリプルネガティブ乳癌としてさらに定義される、請求項2記載の方法。
- 癌が肺癌である、請求項1記載の方法。
- 処置前に対象が脳転移を有することが未知であった、請求項1記載の方法。
- 処置前に対象が1つまたは複数の脳転移を有することが既知であった、請求項1記載の方法。
- 対象がヒトである、請求項1記載の方法。
- キナーゼ阻害剤がCDK5またはLIMK2を標的とする、請求項1記載の方法。
- キナーゼ阻害剤がCDK5を標的とする、請求項1記載の方法。
- キナーゼ阻害剤がLIMK2を標的とする、請求項1記載の方法。
- キナーゼ阻害剤がsiRNAまたはmiRNAである、請求項1記載の方法。
- キナーゼ阻害剤が選択的薬理学的阻害剤である、請求項1記載の方法。
- CDK5のキナーゼ阻害剤が、ディナシクリブ、ビス-インドールインディルビン、(S)-CR8、ケンパウロン、PHA-793887、AT7519、ロスコビチン、ミルシクリブ(milciclib)、SNS-032、またはオロモウシンである、請求項9記載の方法。
- LIMK2のキナーゼ阻害剤が、BMS-5、Pyr-1、またはT56-LIMKiである、請求項10記載の方法。
- BTKのキナーゼ阻害剤が、イブルチニブ、アカラブルチニブ、ONO-4059、スペブルチニブ、BGB-3111、またはHM71224である、請求項1記載の方法。
- CAMK4のキナーゼ阻害剤がKN-93である、請求項1記載の方法。
- MAP2K7のキナーゼ阻害剤がDTP3である、請求項1記載の方法。
- PMVKのキナーゼ阻害剤が、CDDD_1633、CSDDD_2260、CSDDD_2419、またはルテオリンである、請求項1記載の方法。
- PRKCIのキナーゼ阻害剤が、リドーラまたはRXDX-108である、請求項1記載の方法。
- キナーゼ阻害剤を脳へ直接送達する、請求項1〜19のいずれか一項記載の方法。
- キナーゼ阻害剤を、経口的に、局所的に、静脈内に、腹腔内に、筋肉内に、内視鏡的に、経皮的に、皮下に、局部的に、または直接注射によって投与する、請求項1〜19のいずれか一項記載の方法。
- キナーゼ阻害剤を静脈内投与する、請求項1〜19のいずれか一項記載の方法。
- キナーゼ阻害剤を髄腔内または鼻腔内投与する、請求項1〜19のいずれか一項記載の方法。
- 少なくとも第2の治療剤を投与する工程をさらに含む、請求項1〜19のいずれか一項記載の方法。
- 第2の治療剤が、化学療法、放射線療法、遺伝子療法、手術、ホルモン療法、抗血管新生療法、またはサイトカイン療法である、請求項24記載の方法。
- 第2の治療剤が、放射線療法、化学療法、免疫療法、および/または代謝調節である、請求項24記載の方法。
- 第2の治療剤をキナーゼ阻害剤と同時に投与する、請求項24記載の方法。
- 第2の治療剤をキナーゼ阻害剤に連続して投与する、請求項24記載の方法。
- 癌を有する対象における脳転移を処置するための方法であって、
該方法が、有効量のキナーゼ阻害剤と少なくとも第2の抗癌剤とを組み合わせてその必要がある対象へ投与する工程を含み、該キナーゼ阻害剤が、PCTK1、SPHK1、FRK、MAPK12、ERK5、MAP2K7、UCK2、DAK、およびPRKCDからなる群より選択されるキナーゼを標的とする、前記方法。 - 癌が乳癌である、請求項29記載の方法。
- 乳癌がトリプルネガティブ乳癌としてさらに定義される、請求項30記載の方法。
- 癌が肺癌である、請求項29記載の方法。
- 処置前に対象が脳転移を有することが未知であった、請求項1記載の方法。
- 処置前に対象が1つまたは複数の脳転移を有することが既知であった、請求項29記載の方法。
- 対象がヒトである、請求項29記載の方法。
- キナーゼ阻害剤が、PCTK1、SPHK1、MAPK12、またはCDK5を標的とする、請求項29記載の方法。
- キナーゼ阻害剤がPCTK1を標的とする、請求項29記載の方法。
- キナーゼ阻害剤がSPHK1を標的とする、請求項29記載の方法。
- キナーゼ阻害剤がMAPK12を標的とする、請求項29記載の方法。
- MAPK12のキナーゼ阻害剤が、SB 203580、ドラマピモド(doramapimod)、またはLY2228820である、請求項29記載の方法。
- PCTK1のキナーゼ阻害剤が、インディルビンE804、ダブラフェニブ、またはレバスチニブ(rebastinib)である、請求項29記載の方法。
- PCTK1のキナーゼ阻害剤がレバスチニブである、請求項29記載の方法。
- SPHK1のキナーゼ阻害剤が、BML-258、SKI III、SKI 5C、MP A08、SKI 178、PF-543、フィンゴリモド、またはサフィンゴールである、請求項29記載の方法。
- SPHK1のキナーゼ阻害剤が、フィンゴリモドまたはサフィンゴールである、請求項29記載の方法。
- CDK5のキナーゼ阻害剤が、ディナシクリブ、PHA-793887、AT7519、CYC-065、またはDCAM-422である、請求項29記載の方法。
- CDK5のキナーゼ阻害剤が、CYC-065またはDCAM-422である、請求項29記載の方法。
- ERK5のキナーゼ阻害剤が、ERK5-IN-1、BIX 02189、XMD17-109、またはXMD 8-92である、請求項29記載の方法。
- FRKのキナーゼ阻害剤が、ダサチニブ、モテサニブ、ドラマピモド、ペリチニブ(pelitinib)、ソラフェニブ、バンデタニブ、カネルチニブ、またはイマチニブである、請求項29記載の方法。
- PAK4のキナーゼ阻害剤が、PF-3758309、LCH-7749944、グラウカルビノン、KY-04031、KY-04045、1-フェナントリル-テトラヒドロイソキノリン誘導体、(-)-β-ヒドラスチン、Inka1、GL-1196、またはGNE-2861である、請求項29記載の方法。
- UCK2のキナーゼ阻害剤が、フラボカワインBまたはアルピネチンである、請求項29記載の方法。
- キナーゼ阻害剤を、経口的に、局所的に、静脈内に、腹腔内に、筋肉内に、内視鏡的に、経皮的に、皮下に、局部的に、または直接注射によって投与する、請求項29〜51のいずれか一項記載の方法。
- キナーゼ阻害剤を静脈内投与する、請求項29〜51のいずれか一項記載の方法。
- キナーゼ阻害剤を髄腔内または鼻腔内投与する、請求項29〜51のいずれか一項記載の方法。
- 第2の治療剤が、化学療法、放射線療法、遺伝子療法、手術、ホルモン療法、抗血管新生療法、またはサイトカイン療法である、請求項29〜51のいずれか一項記載の方法。
- 第2の治療剤が、放射線療法、化学療法、免疫療法、および/または代謝調節である、請求項29〜51のいずれか一項記載の方法。
- 第2の治療剤をキナーゼ阻害剤と同時に投与する、請求項29〜51のいずれか一項記載の方法。
- 第2の治療剤をキナーゼ阻害剤に連続して投与する、請求項29〜51のいずれか一項記載の方法。
- 対象における転移を阻害するための方法であって、
対照と比較した場合に、ADCK4、BTK、CAMK4、CDK5、CDK5R1、CLK3、DAK、FRK、LIMK2、MAP2K7、MAPK12、MAPK7、PAK4、PCTK1、PMVK、PRKACB、PRKACG、PRKCD、PRKCI、SPHK1、TSSK6、UCK2、およびZC3HC1からなる群より選択される少なくとも2個のキナーゼの活性が増加していると同定された対象へ、キナーゼ阻害剤を投与する工程を含む、前記方法。 - 増加した活性が、増加した発現レベル、翻訳後修飾、または細胞内局在化の結果である、請求項58記載の方法。
- 増加した活性が、増加した発現レベルによって測定される、請求項59記載の方法。
- 対象が乳癌または肺癌を有する、請求項58記載の方法。
- 転移が脳転移としてさらに定義される、請求項58記載の方法。
- 対象が、対照と比較して、ADCK4、BTK、CAMK4、CDK5、CDK5R1、CLK3、DAK、FRK、LIMK2、MAP2K7、MAPK12、MAPK7、PAK4、PCTK1、PMVK、PRKACB、PRKACG、PRKCD、PRKCI、SPHK1、TSSK6、UCK2、およびZC3HC1からなる群より選択される少なくとも5個のキナーゼの活性が増加していると同定される、請求項58記載の方法。
- 対象が、対照と比較して、ADCK4、BTK、CAMK4、CDK5、CDK5R1、CLK3、DAK、FRK、LIMK2、MAP2K7、MAPK12、MAPK7、PAK4、PCTK1、PMVK、PRKACB、PRKACG、PRKCD、PRKCI、SPHK1、TSSK6、UCK2、およびZC3HC1からなる群より選択される少なくとも15個のキナーゼの発現が増加していると同定される、請求項58記載の方法。
- 対象が、対照と比較して、ADCK4、BTK、CAMK4、CDK5、CDK5R1、CLK3、DAK、FRK、LIMK2、MAP2K7、MAPK12、MAPK7、PAK4、PCTK1、PMVK、PRKACB、PRKACG、PRKCD、PRKCI、SPHK1、TSSK6、UCK2、およびZC3HC1からなる群より選択される少なくとも20個のキナーゼの発現が増加していると同定される、請求項58記載の方法。
- 癌を有する対象における脳転移を処置するための有効量のキナーゼ阻害剤を含む組成物であって、該キナーゼ阻害剤が、ADCK4、BTK、CAMK4、CDK5、CDK5R1、CLK3、LIMK2、PAK4、PMVK、PRKACB、PRKACG、PRKCI、TSSK6、およびZC3HC1からなる群より選択されるキナーゼを標的とする、前記組成物。
- 癌を有する対象における脳転移を処置するための有効量のキナーゼ阻害剤および抗癌剤を含む組成物であって、該キナーゼ阻害剤が、PCTK1、SPHK1、FRK、MAPK12、ERK5、MAP2K7、UCK2、DAK、およびPRKCDからなる群より選択されるキナーゼを標的とする、前記組成物。
- 癌が乳癌である、請求項66または67記載の組成物。
- 乳癌がトリプルネガティブ乳癌としてさらに定義される、請求項66または67記載の方法。
- 癌が肺癌である、請求項66または67記載の方法。
- 対象が、処置前に脳転移を有することが未知であった、請求項66または67記載の方法。
- 対象が、処置前に1つまたは複数の脳転移を有することが既知であった、請求項66または67記載の方法。
- 対象がヒトである、請求項66または67記載の方法。
- 少なくとも第2の抗癌剤を投与する工程をさらに含む、請求項66記載の方法。
- 第2の抗癌剤が、化学療法、放射線療法、遺伝子療法、手術、ホルモン療法、抗血管新生療法、またはサイトカイン療法である、請求項67または74記載の方法。
- 第2の治療剤が、放射線療法、化学療法、免疫療法、または代謝調節である、請求項67または74記載の方法。
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