JP2018507249A - Ras変異と関連するがんの治療方法 - Google Patents
Ras変異と関連するがんの治療方法 Download PDFInfo
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- JP2018507249A JP2018507249A JP2017546913A JP2017546913A JP2018507249A JP 2018507249 A JP2018507249 A JP 2018507249A JP 2017546913 A JP2017546913 A JP 2017546913A JP 2017546913 A JP2017546913 A JP 2017546913A JP 2018507249 A JP2018507249 A JP 2018507249A
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
本願は、2015年3月6日に出願された米国特許仮出願第62/129,654号および2015年11月2日に出願された米国特許仮出願第62/249,788号(これらの開示は全文を参照することにより本明細書に組み入れられるものとする)の優先権を主張する。
本発明は、化学および医薬の分野に関する。より詳細には、本発明は、プリナブリンを用いた、RAS変異に関連するがんの治療方法に関する。
プリナブリンを、米国特許第7,064,201号および同第7,919,497号(その全文を参照することにより本明細書に組み入れられるものとする)に記載の方法および手順に従って容易に製造できる。いくつかの実施形態は、発がん性RAS変異と関連するがん治療のためのプリナブリンの使用に関する。
いくつかの実施形態は、対象のRASタンパク質の変異型を発現することを特徴とするがん治療のためのプリナブリンの使用に関する。いくつかの実施形態は、RAS変異を有する細胞の増殖阻害のためのプリナブリンの使用に関する。いくつかの実施形態は、RAS変異を有する細胞のアポトーシス誘導のためのプリナブリンの使用に関する。いくつかの実施形態は、対象のRASタンパク質の変異型を発現することを特徴とするがんの進行阻
害のためのプリナブリンの使用に関する。いくつかの実施形態では、RASタンパク質はKRASタンパク質である。いくつかの実施形態では、RASタンパク質はNRASタンパク質である。
別段の定義がない限り、本明細書で使用する全技術および科学用語は、本開示に属する分野の当業者により共通に理解されるのと同じ意味を有する。全特許、出願、公開された出願、および他の出版物は、その全文を参照することにより組み入れられる。本明細書の用語の複数の定義がある場合、特に指定されない限り、本節中のものが適用される。
号(その全文を参照することにより本明細書に組み入れられる)に記載されているように、多くのこのような塩は当技術分野で公知である。
組み入れられる)に記載されている。
よびメチルセルロースなどのセルロースおよびその誘導体;トラガント末;麦芽;ゼラチン;タルク;ステアリン酸およびステアリン酸マグネシウムなどの固形潤滑剤;硫酸カルシウム;ピーナッツ油、綿実油、ゴマ油、オリーブ油、トウモロコシ油およびカカオ油などの植物油;プロピレングリコール、グリセリン、ソルビトール、マンニトールおよびポリエチレングリコールなどのポリオール類;アルギン酸;ツイーンなどの乳化剤;ラウリル硫酸ナトリウムなどの湿潤剤;着色剤;香味料;打錠薬剤、安定剤;酸化防止剤;防腐剤;発熱物質なしの水;等張食塩水;およびリン酸緩衝液である。
(2004)。
ール、ペパーミント、および果実フレーバーなどの甘味料および香料はチュアブル錠用に有用なアジュバントである。カプセル剤は、通常、上記に開示の1つ以上の固体希釈剤を含む。担体成分の選択は、味、費用、および保存性など、重要でない二次的考察に依存し、当業者により容易に製造できる。
では、プリナブリンまたは他の治療薬の単回用量は、体表面積の約5mg/m2〜約150mg/m2、体表面積の約5mg/m2〜約100mg/m2、体表面積の約10mg/m2〜約100mg/m2、体表面積の約10mg/m2〜約80mg/m2、体表面積の約10mg/m2〜約50mg/m2、体表面積の約10mg/m2〜約40mg/m2、体表面積の約10mg/m2〜約30mg/m2、体表面積の約13.5mg/m2〜約100mg/m2、体表面積の約13.5mg/m2〜約80mg/m2、体表面積の約13.5mg/m2〜約50mg/m2、体表面積の約13.5mg/m2〜約40mg/m2、体表面積の約13.5mg/m2〜約30mg/m2、体表面積の約15mg/m2〜約80mg/m2、体表面積の約15mg/m2〜約50mg/m2、体表面積の約15mg/m2〜約30mg/m2であり得る。いくつかの実施形態では、プリナブリンまたは他の治療薬の単回用量は、体表面積の約13.5mg/m2〜約30mg/m2であり得る。いくつかの実施形態では、プリナブリンまたは他の治療薬の単回用量は、体表面積の約5mg/m2、約10mg/m2、約12.5mg/m2、約13.5mg/m2、約15mg/m2、約17.5mg/m2、約20mg/m2、約22.5mg/m2、約25mg/m2、約27.5mg/m2、約30mg/m2、約40mg/m2、約50mg/m2、約60mg/m2、約70mg/m2、約80mg/m2、約90mg/m2、または約100mg/m2であり得る。
び生物学的療法などの治療と組み合わせて投与または使用できる。
いくつかの実施形態は、それを必要とする対象にプリナブリンを投与することを含む、RASタンパク質の変異型を発現することを特徴とするがんの治療方法に関する。いくつかの実施形態は、それを必要とする対象にプリナブリンを投与することを含む、発がん性RAS変異と関連するがんの治療方法に関する。
施形態では、KRASタンパク質の変異型は、G12、G13、A59、Q61、K117およびA146から選択される1つ以上のアミノ酸位置において変異を有する。いくつかの実施形態では、KRASタンパク質の変異型は、G12C、G12R、G12S、G12A、G12D、G12V、G13C、G13R、G13S、G13A、G13D、G13V、A59E、A59G、A59T、Q61K、Q61L、Q61R、Q61H、K117N、K117R、K117E、A146P、A146TおよびA146Vから成る群から選択される1つ以上のアミノ酸置換を有する。いくつかの実施形態では、KRASタンパク質の変異型は、G12、G13、A59およびQ61から選択される1つ以上のアミノ酸位置において変異を有する。いくつかの実施形態では、KRASタンパク質の変異型は、G12C、G12R、G12S、G12A、G12D、G12V、G13C、G13R、G13S、G13A、G13D、A59E、A59G、A59T、Q61K、Q61L、Q61RおよびQ61Hから成る群から選択される1つ以上のアミノ酸置換を有する。いくつかの実施形態では、KRASタンパク質の変異型は、G12、G13およびD153から選択される1つ以上のアミノ酸位置において変異を有する。いくつかの実施形態では、KRASタンパク質の変異型は、G12A、G12C、G12D、G12V、G12S、G13D、およびD153Vから成る群から選択される1つ以上のアミノ酸置換を有する。いくつかの実施形態では、KRASタンパク質の変異型は、G12C、G12SおよびD153Vから選択される1つ以上のアミノ酸置換を有する。
RAS変異を有する細胞の増殖阻害方法に関する。いくつかの実施形態は、細胞をプリナブリンと接触させることを含む、NRAS変異を有する細胞のアポトーシス誘導方法に関する。いくつかの実施形態は、細胞をプリナブリンと接触させることを含む、対象のNRASの変異型を発現することを特徴とするがんの進行阻害方法に関する。
RAS遺伝子またはそのフラグメントを増幅し;および(iv)増幅したRAS遺伝子中に変異があるかどうか検出することにより患者がRAS変異を特徴とするがんを有するかどうかを決定することにより同定される。RAS変異の検出方法の例としては、拡大難治性変異システム(ARMS)PCR、BEAMingアッセイ、デジタルPCR、および他の適切なプライマー、およびシークエンシングまたはPCR用プローブが挙げられるが、これに限定されない。
GIy 12 Asp(GGT>GAT)GIy 12 Arg(GG1>CGT)
GIy 12 Ala(GGT>GCT)GIy 12 Cys(GGT>TGT)
GIy 12 VaI(GGT>GTT)GIy 13 Asp(GGOGAC)
Gly l2 Ser(GGT>AGT)
ドン変異に基づいて設計できる。
2〜10%FBSを添加したそのそれぞれの適切な成長培地内で全セルラインを成長し、37℃、5%CO2の雰囲気で収容した。
タを表した。未治療コントロールの平均発光値によりプリナブリンで治療した試料の平均発光値を割ることによって細胞の生存率を決定した。プリナブリン治療試料およびコントロールの阻害濃度(IC50)値を、Prism6ソフトウェア(GraphPad Software, Inc.)を用いて、非線形回帰分析を用いたデータのカーブフィッティングにより推定した。
プリナブリンおよびドセタキセルの組合せを試験し、その活性を、A549(KRAS
G12S)ヒト肺腫瘍異種移植モデルにおける標準化学療法薬ドセタキセルと比較した。実験データから、A549モデルにおいてドセタキセルと併用したプリナブリンの有望な相加効果または相乗効果を決定した。
約20gの重量で5〜6週齢の雌ヌードマウス(nu/nu)を、Harlan,Inc.(ウィスコンシン州マディソン)から得た。A549ヒト肺腫瘍セルラインを、アメリカ培養細胞系統保存機関(ATCC)から得た。A549ヒト肺腫瘍セルラインは、KRAS G12Sにおいて変異を有した。腫瘍は、58歳白人男性の肺がん性組織の移植片培養に由来する。動物は、ヌードマウスホスト内において皮下増殖腫瘍から収穫したA549ヒト腫瘍がんのフラグメントを用いてトロカールにより皮下(s.c.)に移植した。腫瘍が約46mgの大きさになった場合(移植後18日)、動物を治療群およびコントロール群にペアマッチングした。ネガティブコントロール群は8匹の腫瘍マウスを含み、他の全群は9匹の腫瘍マウスを含んだ。各マウスの耳にタグを付け、実験中ずっと個別にフォローした。非GLP設定において試験を実施した。ペアマッチング後1日目に初回投与した。2つの異なるスケジュール−1日目、4日目、8日目、11日目および15日目、ならびにqdx5(5日間毎日1回投与)で、7.5mg/kgのプリナブリンを腹腔内投与した。ネガティブコントロールの役割のため、12.5%ジメチルスルホキシド(DMSO)、5%クレモフォール、および82.5%ピーナッツ油を混合して腹腔内投与した;qdx5。12.5mg/kgで、1日目、3日目、および5日目にドセタキセル(Aventis)を静脈内投与し、ポジティブコントロールの役割のため、wklyx3で100mg/kgを腹腔内投与した。また、qdx5スケジュールで7.5mg/kgのプリナブリンを、単剤と同じ用量、経路、およびスケジュールでドセタキセルと併用して投与した。プリナブリンおよびドセタキセル併用群では、プリナブリンの15〜30分前にドセタキセルを投与した。
GraphPad Prism(登録商標)ソフトウェア(Machintoshバージョン3.0)を用いた片側t検定を使用してp値算出した。
ネガティブコントロール群は、870.4mg±305.1の56日目最終平均腫瘍重量を有した。ドセタキセル(12.5mg/kg;静脈内;1日目、3日目、5日目)は、試験のポジティブコントロールの役割を果たし、それぞれ655.1mg±109.2および691.4±175.8の最終平均腫瘍重量を有した。これは、媒体コントロール群と比較してドセタキセルが26.1%のTGIになり、過去実施したA549試験で見られた期待される活性範囲内であった。ドセタキセル群またはイリノテカン群で観察された中毒死はなかった。
1〜5日目に7.5mg/kgのプリナブリンを腹腔内投与することにより、1525.7mg±355.3の平均最終腫瘍重量となった。プリナブリン(7.5mg/kg;1〜5日目)およびドセタキセル(12.5mg/kg;静脈内;1日目、3日目、5日目)の併用群は、265.8mg±113.1の56日目最終平均腫瘍重量を有した。これは、74.3%のTGIという結果であった。この併用は、655.1mg±109の平均最終腫瘍重量を有したドセタキセル治療群より優れており、併用群とドセタキセル単剤群との差は、統計的に有意(p<0.05)であった。
使用したグリオーマのマウスモデルは、グリオブラストーマ(GBM)の前神経分子サブグループを模倣するグリオーマのPDGF誘導GEMMであった。このモデルは、体細胞特異性遺伝子導入に基づき;複製可能なALVスプライスアクセプター(RCAS)レトロウイルスシステムは、細胞型特異的に分化の厳密に調節されたウインドウ内の特定の遺伝子変異の滴下注入を可能とした。RCAS/tv−aシステムは、RCASレトロウイルスベクターを使用して、特定の細胞集団においてRCAS受容体(tv−a)を発現するように遺伝子組換えしたマウスを感染させた。ここで、脳内のネスチン発現細胞にPDGFをRCAS媒介導入することにより、グリオーマを生成した。脳内の幹細胞/前駆細胞集団においてネスチンを発現し、ヒトおよびマウス脳腫瘍の両方において血管周辺部(PVN)にあるがん幹細胞のマーカーであることを示した。PDGF誘導グリオーマは、感染後4〜5週間までにInk4a−arf−/−欠失と組み合わせた場合、完全な浸透率を有して発生した。これらの腫瘍は、CDKN2A(p16INK4Aおよびp14ARFの両方をコードする)欠失が「前神経」ヒトグリオーマの56%で観察されたGBMの「前神経」サブタイプを密接に模倣した。シェーレル構造、微小血管増殖および偽柵状ネクローシスなどのヒトグリオーマを規定する腫瘍細胞構造を、図1a〜1dに示すようにこのGEMMにおいて再形成した。さらに、グリオーマ細胞は白質トラックに沿って遊走し、ニューロンおよび血管を囲み、軟膜下の空間内の脳の縁に蓄積した。これに関して、グリオーマのPDGF誘導GEMMは、PN−GBMに酷似し、腫瘍内微小環境において腫瘍細胞と非新生細胞との間の相互作用を規定する優れた実験システムを示す。
G12D変異KRASを発現するPDGF誘導グリオーマを有するマウスを、実施例3に記載の手順を用いて準備してこの実験で使用した。4〜6週齢ネスチン−tv−a/i
nk4a−arf−/−マウスをイソフルランで麻酔し、Df−1細胞にトランスフェクトしたRCAS−PDGF−B−HA、RCAS−KRASを注射した。ハミルトンシリンジに装着した26ゲージニードルにより定位フレームを用いて、2×105RCAS−PDGF−B−HA/RCAS−KRASの1:1混合物1マイクロリットルをマウスに注射した。細胞を右前頭葉内に注射したが、十字縫合1.75mm、側方−0.5mm、および深さ2mmに調整する。マウスを重量減少に対して注意深くモニターし、合計2連続日にわたって>0.3グラム減少した場合または腫瘍の外的徴候を示した場合試験を供した。
プリナブリンおよびイリノテカンの組合せを試験し、その活性を、HCT−15(KRAS変異G13D;P53変異S241F)ヒト結腸腫瘍異種移植モデルにおける標準化学療法薬イリノテカンと比較した。実験データから、HCT−15モデルにおいてイリノテカンと併用したプリナブリンの相乗効果を決定した。
雌胸腺欠損ヌードマウス(Hsd:Athymic Nude−Foxn1nu)は、Harlan(インディアナ州インディアナポリス)により供給された。マウスを4週齢で受け取った。全マウスを取り扱う前に気候順化した。HCT−15ヒト結腸腫瘍セルラインをATCC(バージニア州マナサス)から受け取った。10%ウシ胎児血清(FBS:Seradigm;ペンシルバニア州ラドナー)を添加したRPMI−1640(Lonza;メリーランド州ウォーカーズビル)で培養液を維持し、5%CO2雰囲気中に収容した。充分な量の細胞を回収するまで、1:10分割比で組織培養フラスコ内に培養液を広げた。HCT−15ヒト結腸腫瘍セルラインは、KRAS G13DおよびP53 S241Fにおいて変異を有した。
lの濃度まで希釈した。3週間週1回100mg/kgの用量でイリノテカンを腹腔内投与し、ポジティブコントロールとした。また、単剤と同じ用量、経路、およびスケジュールでイリノテカンと併用してプリナブリンを投与した。プリナブリンおよびイリノテカン併用群では、プリナブリンの120分前にイリノテカンを投与した。
ネガティブコントロール群は、1701.4mm3±178.0の27日目最終平均腫瘍量を有した。イリノテカン(100mg/kg;腹腔内;1日目、8日目、15日目)は、試験のポジティブコントロールの役割を果たし、1196.2mm3±121.7の最終平均腫瘍量を有した。媒体ネガティブコントロール群と比較して、これは、イリノテカンについて31.8%のTGIという結果であった。ネガティブコントロールまたはポジティブ群で観察された中毒死はなかった。
を示した(58.8%対31.8%)。この結果は、イリノテカン単剤と比較した場合、プリナブリンとイリノテカンの併用の強力な腫瘍増殖阻害は、HCT−15(KRAS G13D)ヒト肺腫瘍異種移植モデルにおいてイリノテカンと併用したプリナブリンの有望な相加効果または相乗効果を示していることを示した。
プリナブリンおよびイリノテカンの組合せを試験し、その活性を、LoVo(KRAS変異 p.G13D)ヒト結腸腫瘍異種移植モデルにおけるイリノテカン単独と比較した。実験データから、LoVoモデルにおいてイリノテカンと併用したプリナブリンの有望な相加効果または相乗効果を決定した。
価を行った。
Claims (34)
- それを必要とする対象にプリナブリンを投与することを含む、RASタンパク質の変異型を発現することを特徴とするがんの治療方法。
- 前記RASタンパク質が、KRAS、NRASまたはHRASタンパク質である、請求項1に記載の方法。
- 前記RASタンパク質の変異型が、KRASタンパク質の変異型である、請求項2に記載の方法。
- 前記がんが、結腸直腸がん、膵がん、腎がん、肺がん、肝がん、乳がん、前立腺がん、胃腸がん、腹膜がん、メラノーマ、子宮内膜がん、卵巣がん、子宮頚がん、子宮がん、膀胱がん、グリオブラストーマ、転移性脳腫瘍、唾液腺がん、甲状腺がん、脳がん、リンパ腫、骨髄腫、および頭頚部がんから選択される、請求項1〜3のいずれか一項に記載の方法。
- 前記がんが、扁平上皮がん、小細胞肺がん、非小細胞肺がん、肺腺がん、肺の扁平上皮がん、肝細胞がん、結腸がん、子宮内膜がん、および肝細胞がんから選択される、請求項1〜4のいずれか一項に記載の方法。
- 前記がんが、結腸直腸がん、前立腺がん、乳がん、肺がん、子宮内膜がん、多発性骨髄腫、膵がん、腎がん、およびグリオブラストーマから選択される、請求項1〜5のいずれか一項に記載の方法。
- 前記がんが、非小細胞肺がん、膵がん、およびグリオブラストーマから選択される、請求項6に記載の方法。
- 前記がんが、非小細胞肺がんである、請求項7に記載の方法。
- 前記KRASタンパク質が、コドン12、13、59、61、および146から選択される1つ以上の位置において変異を含む、請求項3〜8のいずれか一項に記載の方法。
- 前記KRASタンパク質の変異型が、G12、G13、S17、P34、A59、およびQ61から選択される1つ以上のアミノ酸位置において変異を含む、請求項3〜8のいずれか一項に記載の方法。
- 前記KRASタンパク質の変異型が、G12C、G12S、G12R、G12F、G12L、G12N、G12A、G12D、G12V、G13C、G13S、G13D、G13V、G13P、S17G、P34S、A59E、A59G、A59T、Q61K、Q61L、Q61R、およびQ61Hから成る群から選択される1つ以上のアミノ酸置換を含む、請求項10に記載の方法。
- 前記KRASタンパク質の変異型が、G12、G13、A59、Q61、K117およびA146から選択される1つ以上のアミノ酸位置において変異を含む、請求項3〜8のいずれか一項に記載の方法。
- 前記KRASタンパク質の変異型が、G12C、G12R、G12S、G12A、G12D、G12V、G13C、G13R、G13S、G13A、G13D、G13V、A59E、A59G、A59T、Q61K、Q61L、Q61R、Q61H、K117N、A
146P、A146TおよびA146Vから成る群から選択される1つ以上のアミノ酸置換を含む、請求項12に記載の方法。 - 前記KRASタンパク質の変異型が、G12、G13、A59、およびQ61から選択される1つ以上のアミノ酸位置において変異を含む、請求項3〜8のいずれか一項に記載の方法。
- 前記KRASタンパク質の変異型が、G12C、G12R、G12S、G12A、G12D、G12V、G13C、G13R、G13S、G13A、G13D、A59E、A59G、A59T、Q61K、Q61L、Q61RおよびQ61Hから成る群から選択される1つ以上のアミノ酸置換を含む、請求項14に記載の方法。
- 前記KRASタンパク質の変異型が、G12、G13、およびD153から選択される1つ以上のアミノ酸位置において変異を含む、請求項3〜8のいずれか一項に記載の方法。
- 前記KRASタンパク質の変異型が、G12A、G12C、G12D、G12V、G12S、G13D、およびD153Vから成る群から選択される1つ以上のアミノ酸置換を含む、請求項16に記載の方法。
- 前記KRASタンパク質の変異型が、G12C、G12S、およびD153Vから選択される1つ以上のアミノ酸置換を含む、請求項17に記載の方法。
- 前記対象が、KRAS変異を有するかどうかを決定することを含む、請求項1〜18のいずれか一項に記載の方法。
- 前記RASタンパク質の変異型が、NRASタンパク質の変異型である、請求項2に記載の方法。
- 前記NRASタンパク質が、コドン12、13、59、61、および146から選択される1つ以上の位置において変異を含む、請求項20に記載の方法。
- 前記NRASタンパク質の変異型が、Q61またはA146において変異を含む、請求項21に記載の方法。
- 前記NRASタンパク質の変異型が、Q61K、Q61H、Q61R、Q61L、Q61N、Q61E、Q61P、A146T、A146P、およびA146Vから選択される1つ以上のアミノ酸置換を含む、請求項22に記載の方法。
- 前記対象が、NRAS変異を有するかどうかを決定することを含む、請求項20〜23のいずれか一項に記載の方法。
- 前記対象が、HRAS変異を有するかどうかを決定することを含む、請求項20〜23のいずれか一項に記載の方法。
- プリナブリンを追加の活性薬剤と同時投与することを含む、請求項1〜25のいずれか一項に記載の方法。
- 前記追加の活性薬剤が追加の治療薬である、請求項26に記載の方法。
- 前記追加の治療薬がドセタキセルであり、前記がんがヒト非小細胞肺がんである、請求項27に記載の方法。
- 前記追加の治療薬がイリノテカンであり、前記がんがヒト結腸がんである、請求項27に記載の方法。
- 細胞をプリナブリンと接触させることを含む、RAS変異を有する前記細胞の増殖阻害方法。
- 前記接触が、前記細胞を有する対象にプリナブリンを投与することを含む、請求項30に記載の方法。
- 細胞をプリナブリンと接触させることを含む、RAS変異を有する前記細胞のアポトーシス誘導方法。
- 前記接触が、それを必要とする対象にプリナブリンを投与することを含む、請求項32に記載の方法。
- それを必要とする対象にプリナブリンを投与することを含む、対象のRASタンパク質の変異型を発現することを特徴とするがんの進行阻害方法。
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