JP2018522038A - がんの処置のための併用療法 - Google Patents
がんの処置のための併用療法 Download PDFInfo
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Abstract
Description
技術分野
本発明は、一般に、サイクリン依存性キナーゼインヒビターおよびDNAメチルトランスフェラーゼインヒビターの投与によってがんを処置する方法に関する。
骨髄異形成症候群(MDS)は、健全な血球数を産生することができないことによって特徴付けられる種々の骨髄障害である。頻繁に(およそ30%)MDSは急性骨髄性白血病(AML)に進行し、このAMLは、ほぼ治癒しないまま維持され、生存率が比較的低い。MDSの処置法の選択肢の1つとしては、メチル化阻害剤(hypomethylating agent)であるアザシチジンおよびデオキシアザシチジン(デシタビン)であり、これらのメチル化阻害剤は、以下の2つの主な(principle)機序によって作用する:1)DNAメチルトランスフェラーゼ(methyltransferease)を阻害し、それにより、重要な腫瘍抑制遺伝子を活性化させる機序;および2)複製DNA鎖への組み込み後にDNAを直接損傷させる機序。これらの機序のうちの2つ目によってプログラム細胞死経路(アポトーシス)が活性化され、この経路は、重要なアポトーシス制御タンパク質(MCL−1(アポトーシス制御タンパク質のBH3ファミリーの抗アポトーシスメンバー)が含まれる)の発現レベルにいくらか依存することが示されている。
簡単には、本発明の実施形態は、2つの異なる治療剤の投与を含むがんの処置のための方法を提供する。一実施形態において、本開示は、がんの処置を必要とする哺乳動物においてがんを処置する方法であって、有効量の以下の治療剤:
i)サイクリン依存性キナーゼインヒビター、および
ii)DNAメチルトランスフェラーゼインヒビター
を哺乳動物に投与する工程を含む、方法を提供する。
図面では、同一の参照番号は類似の要素を示す。図中の要素のサイズおよび相対的位置は、必ずしも原寸に比例して描写しておらず、これらの要素のうちのいくつかは、図面の視認性を改善するために任意に拡大し、配置している。さらに、描写した要素の特定の形状は、特定の要素の実際の形状に関する任意の情報を伝達することを意図しておらず、専ら図面の認識を容易にするために選択している。
以下の説明において、本発明の種々の実施形態の充分な理解をもたらすために特定の具体的な詳細な説明を示す。しかしながら、当業者には、本発明がこれらの詳細な説明なしに実施され得ることが理解されよう。
(i)哺乳動物において、該がん、疾患または状態が発生するのを予防すること(特に、このような哺乳動物が該状態に罹りやすいが、該状態を有するとは未だ診断されていない場合);
(ii)該がん、疾患または状態を抑制すること、すなわち、その発症を止めること;
(iii)該がん、疾患または状態を軽減すること、すなわち、該疾患または状態の後退をもたらすこと;あるいは
(iv)該がん、疾患または状態に起因する症状を軽減すること、すなわち、根源的な疾患または状態に取り組まずに痛みを軽減することを含む。本明細書において使用される場合、用語「疾患」および「状態」は互換的に使用され得るか、あるいは、具体的な疾病または状態が既知の原因因子を有していなくともよく(その結果、病因がまだ解明されていない)、したがって、それはまだ疾患と認識されていないが単に望ましくない状態または症候群とだけ認識されており、臨床医によって多かれ少なかれ具体的な1セットの症状が確認されているという点で異なり得る。
特定の実施形態において、本方法は、癌細胞の処置ならびに/または哺乳動物、好ましくはヒトにおけるがんおよび/もしくはその症状の予防、処置、もしくは改善に有用である。したがって、一実施形態において、本開示は、がんの処置を必要とする哺乳動物においてがんを処置する方法であって、治療有効量の以下の治療剤:
i)サイクリン依存性キナーゼインヒビター、および
ii)DNAメチルトランスフェラーゼインヒビター
を哺乳動物に投与する工程を含む、方法を提供する。
他の実施形態は、本開示の方法の実施に有用なキットに関する。例えば、いくつかの実施形態において、サイクリン依存性キナーゼインヒビター、DNAメチルトランスフェラーゼインヒビター、ならびにサイクリン依存性キナーゼインヒビターおよびDNAメチルトランスフェラーゼインヒビターをがんの処置を必要とする哺乳動物に投与するための説明書を含むキットを提供する。いくつかの実施形態において、キット中に存在するサイクリン依存性キナーゼインヒビターは、前述の実施形態のうちのいずれか1つに定義の通りである。他の実施形態において、キットの一部であるDNAメチルトランスフェラーゼインヒビターは、前述の実施形態のうちのいずれかに定義の通りである。なおさらなる実施形態において、キットで処置可能ながんは、前述の実施形態のうちのいずれか1つに定義の通りである。
i)サイクリン依存性キナーゼインヒビター、および
ii)DNAメチルトランスフェラーゼインヒビター
を含む。
アルボシジブは時間および用量依存性様式でMCL−1発現を低下させる
AML細胞株であるMV−4−11は、MCL−1を発現する。MCL−1は、MV−4−11細胞における重要な抗アポトーシスタンパク質である。アルボシジブ(CDK9インヒビター)は、MCL−1の発現を低下させ、このことは論文で既に十分に報告されている。アルボシジブは、MCL−1を用量依存性様式で下方制御する(図1A)。用量依存性は、細胞に0〜8μMの濃度のアルボシジブを投与したときのβ−アクチンと比較したMCL−1の相対発現をモニタリングすることによって観測される。MV4−11細胞を、アルボシジブでin vitroにて16時間処置した。処置後、細胞を回収し、MCL−1発現およびβ−アクチン発現の免疫検出のための標準的なウェスタンブロッティング技術を使用して調製した。0.1μMの投薬量のアルボシジブによってMCL−1発現が低下したのに対して、1μMのアルボシジブによって16時間後に発現が完全に遮断された。
アルボシジブおよびアザシチジンを使用した併用処置および細胞生存率に及ぼすその影響
AML細胞増殖は、アルボシジブおよびアザシチジンの投与によって相乗的に阻害される。細胞生存率に及ぼす単一の薬物および組み合わせの影響を決定するために、アルボシジブを単独およびアザシチジンと組み合わせて使用した。アザシチジンのみを投与した細胞と比較して、細胞にアルボシジブとアザシチジンとの組み合わせを投与した場合に細胞生存率に有意な変化が観測された。
カスパーゼ3/7活性およびアポトーシスに及ぼす併用処置の影響
MV4−11細胞を処置するためにアルボシジブをアザシチジンと組み合わせて使用した。併用処置を、アザシチジンのみを使用した処置と比較した。比較を使用して、カスパーゼ3/7活性およびアポトーシスに及ぼす組み合わせの相乗効果を評価した。5−アザシチジンへの80nMアルボシジブの添加処置により、MV4−11細胞におけるカスパーゼ活性の相乗的増加をもたらす。
アルボシジブおよびデシタビンを使用した併用処置および細胞生存率に及ぼすその影響
図5Aおよび5Bは、MV4−11細胞におけるアルボシジブおよびデシタビンの併用処置由来のデータを示す。MV4−11細胞を、最初に、実施例2の一般的手順にしたがって図5Aに示した濃度のアルボシジブ+デシタビンで96時間処置した。アルボシジブ添加によるIC50(μM)のわずかな低下が観測された。あるいは、MV4−11細胞をアルボシジブで24時間前処置し、次いで、デシタビンでさらに72時間処置した(全部で96時間、図5B)。ここでは、アルボシジブをデシタビンの投与前に投与した場合に、アルボシジブ(100nM)の添加によってデシタビンのIC50(μM)においてほぼ10倍の変化が観測された。
Claims (20)
- がんの処置を必要とする哺乳動物においてがんを処置する方法であって、治療有効量の以下の治療剤:
i)サイクリン依存性キナーゼインヒビター;および
ii)DNAメチルトランスフェラーゼインヒビター
を前記哺乳動物に投与する工程を含む、方法。 - 前記サイクリン依存性キナーゼインヒビターが、Cdk7、Cdk9、またはこれらの両方を阻害する、請求項1に記載の方法。
- 前記サイクリン依存性キナーゼインヒビターがMCL−1の発現を阻害する、請求項1に記載の方法。
- 前記サイクリン依存性キナーゼインヒビターが、アルボシジブ、またはジナシクリブ、またはその薬学的に許容され得る塩である、請求項1に記載の方法。
- 前記DNAメチルトランスフェラーゼインヒビターがアポトーシスを活性化する、請求項1に記載の方法。
- 前記DNAメチルトランスフェラーゼインヒビターがヌクレオシドアナログである、請求項1に記載の方法。
- 前記DNAメチルトランスフェラーゼインヒビターがアザヌクレオシドである、請求項1に記載の方法。
- 前記アザヌクレオシドが、アザシチジン、またはデシタビン、またはその薬学的に許容され得る塩である、請求項7に記載の方法。
- 前記サイクリン依存性キナーゼインヒビターが、前記DNAメチルトランスフェラーゼインヒビターの投与前に前記哺乳動物に投与される、請求項1〜8のいずれか1項に記載の方法。
- 前記DNAメチルトランスフェラーゼインヒビターが、前記サイクリン依存性キナーゼインヒビターの投与後約24〜48時間以内に投与される、請求項9に記載の方法。
- 前記DNAメチルトランスフェラーゼインヒビターが、前記サイクリン依存性キナーゼインヒビターの投与前に前記哺乳動物に投与される、請求項1〜8のいずれか1項に記載の方法。
- 前記がんが血液学的がんである、請求項1〜11のいずれか1項に記載の方法。
- 前記血液学的がんが、急性骨髄性白血病(AML)、多発性骨髄腫、濾胞性リンパ腫、急性リンパ芽球性白血病(ALL)、慢性リンパ性白血病(CLL)、および非ホジキンリンパ腫から選択される、請求項12に記載の方法。
- 前記血液がんが急性骨髄性白血病(AML)である、請求項13に記載の方法。
- 前記血液学的がんが骨髄異形成症候群(MDS)である、請求項12に記載の方法。
- サイクリン依存性キナーゼインヒビター、DNAメチルトランスフェラーゼインヒビター、ならびに前記サイクリン依存性キナーゼインヒビターおよび前記DNAメチルトランスフェラーゼインヒビターをがんの処置を必要とする哺乳動物に投与するための説明書を含むキット。
- 前記サイクリン依存性キナーゼインヒビターが請求項2〜4のいずれか1項に定義の通りである、請求項16に記載のキット。
- 前記DNAメチルトランスフェラーゼインヒビターが請求項5〜8のいずれか1項に定義の通りである、請求項16または17のいずれか1項に記載のキット。
- 前記がんが請求項12〜15のいずれか1項に定義の通りである、請求項16〜18のいずれか1項に記載のキット。
- 薬学的に許容され得る担体または賦形剤、サイクリン依存性キナーゼインヒビター、およびDNAメチルトランスフェラーゼインヒビターを含む医薬組成物。
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CN108289861A (zh) | 2018-07-17 |
WO2017024073A1 (en) | 2017-02-09 |
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AU2016301315A1 (en) | 2018-02-22 |
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HK1254882A1 (zh) | 2019-07-26 |
AU2016301315B2 (en) | 2021-12-23 |
AU2016301315C1 (en) | 2022-07-07 |
US20200054642A1 (en) | 2020-02-20 |
BR112018002427A8 (pt) | 2022-10-18 |
RU2759963C2 (ru) | 2021-11-19 |
JP7083497B2 (ja) | 2022-06-13 |
IL257073A (en) | 2018-03-29 |
US10568887B2 (en) | 2020-02-25 |
JP2021054868A (ja) | 2021-04-08 |
US20200215071A1 (en) | 2020-07-09 |
US10682356B2 (en) | 2020-06-16 |
AU2016301315A8 (en) | 2018-03-15 |
RU2018106886A3 (ja) | 2019-12-31 |
US10835537B2 (en) | 2020-11-17 |
EP3331510A4 (en) | 2019-04-03 |
CA2993659A1 (en) | 2017-02-09 |
MX2018001289A (es) | 2018-04-30 |
KR20180034538A (ko) | 2018-04-04 |
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