JP6289459B2 - PHLDA1又はPIK3C2Bの発現に基づくPI3K/AKT/mTOR阻害剤の治療効果の予測方法 - Google Patents
PHLDA1又はPIK3C2Bの発現に基づくPI3K/AKT/mTOR阻害剤の治療効果の予測方法 Download PDFInfo
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- JP6289459B2 JP6289459B2 JP2015522970A JP2015522970A JP6289459B2 JP 6289459 B2 JP6289459 B2 JP 6289459B2 JP 2015522970 A JP2015522970 A JP 2015522970A JP 2015522970 A JP2015522970 A JP 2015522970A JP 6289459 B2 JP6289459 B2 JP 6289459B2
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- 101000583692 Homo sapiens Pleckstrin homology-like domain family A member 1 Proteins 0.000 title claims description 17
- 101000721645 Homo sapiens Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit beta Proteins 0.000 title claims description 13
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Description
本願は、2013年6月20日に出願した特願2013-129591号明細書(その全体が参照により本明細書中に援用される)の優先権の利益を主張するものである。
(技術分野)
本発明は、PI3K/AKT/mTOR阻害剤を含有する抗腫瘍剤を用いた化学療法に対する治療効果を予測する方法、抗腫瘍剤及びキットに関する。
〔1〕 がん患者の腫瘍細胞におけるPHLDA1及び/又はPIK3C2Bの発現量に基づき、当該がん患者におけるPI3K/AKT/mTOR阻害剤を含有する抗腫瘍剤を用いた化学療法の治療効果を予測する方法。
〔2〕 下記工程(1)及び(2)を含む、〔1〕記載の方法。
(2)上記工程(1)で得られたPHLDA1の発現量が予め設定されたカットオフポイント以下である場合、又は上記工程(1)で得られたPIK3C2Bの発現量が予め設定されたカットオフポイント以上である場合、当該がん患者におけるPI3K/AKT/mTOR阻害剤を含有する抗腫瘍剤を用いた化学療法が十分な治療効果を示す可能性が高いと予測する工程。
〔3〕 PI3K/AKT/mTOR阻害剤が、一般式(I)
R1a、R1b、R1c、R1dのうち少なくとも2つが水素原子を示し、他方がそれぞれ
ハロゲン原子、シアノ基、置換基としてヒドロキシル基を有してもよいC1−6アルキル基、C1−6アルコキシ基、置換基としてヒドロキシル基、アミノ基、置換基を有してもよいモノ又はジ(C1−6アルキル)アミノ基又はモノ又はジ(C1−6アルコキシ)アミノ基のいずれかを有するカルボニル基、不飽和複素環基を示し、
R2は、フェニル基、ピリジル基、又はチエニル基を示し、
R3は、水素原子、メチル基、エチル基、又はシクロプロピル基を示し、
R4は、水素原子、又はヒドロキシ基を示す。)
で表されるイミダゾオキサジン化合物又はその薬学的に許容される塩であるか、
AMG−319、AZD−6482、BYL−719、Copanlisib(BAY−80−6946)、GDC−0032、GDC−0084、GSK−1059615 、GSK−2126458、GSK−2636771、Idelalisib(CAL−101)、IPI−145、MLN−1117(INK−1117)、PA−799(CH−5132799)、Pictilisib(GDC−0941)、Pilaralisib(XL−147)、SF−1126、Sonolisib(PX−866) 、Voxtalisib(SAR−245409、XL−765)、Afuresertib hydrochloride(GSK−2110183 )、ARQ−092、AZD5363、Enzastaurin hydrochloride、GDC−0068、GSK−2141795、GSK690693、LY−2780301、MK−2206、Perifosine、Triciribine phosphate(VQD−002)、AZD−2014、AZD−8055、CC−115、CC−223、DS−3078、Everolimus、Temsirolimus、ME−344、MLN−0128(INK−128)、OSI−027、PWT−33597、Ridaforolimus、Sirolimus、Dactolisib(BEZ235) 、DS−7423、GDC−0980、NVP−BGT−226、PF−04691502、PF−05212384(PKI−587)、又はPWT−33597である〔1〕又は〔2〕記載の方法。
〔4〕 一般式(I)で表されるイミダゾオキサジン化合物が、A、B、C、及びDは、それぞれC−R1a、C−R1b、C−R1c、及びC−R1dを示すか、或いは前記A、B、C、Dのうちいずれか1又は2つがN原子に置換されていることを示し、
R1a、R1b、R1c、R1dのうち少なくとも2つが水素原子を示し、他方がそれぞれ塩素原子、フッ素原子、シアノ基、メチル基、ヒドロキシメチル基、メトキシ基、エトキシ基、カルボキシル基、カルバモイル基、メチルアミノカルボニル基、エチルアミノカルボニル基、ヒドロキシエチルアミノカルボニル基、エトキシアミノカルボニル基、ピラゾリル基を示し、
R2は、フェニル基、ピリジル基、又はチエニル基を示し、
R3は、水素原子、メチル基、エチル基、又はシクロプロピル基を示し、
R4は、水素原子、又はヒドロキシ基を示す化合物である、〔3〕記載の方法。
〔5〕 一般式(I)で表されるイミダゾオキサジン化合物が、次の(a)〜(t)のいずれかの化合物である〔3〕又は〔4〕記載の方法。
(b)トランス−3−アミノ−1−シクロプロピル−3−(4−(10−フルオロ−3−(ピリジン−4−イル)−5H−ベンゾ[e]イミダゾ[1,2−c][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(c)トランス−3−アミノ−1−シクロプロピル−3−(4−(3−フェニル−5H−ベンゾ[e]イミダゾ[1,2−c][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(d)トランス−3−アミノ−1−シクロプロピル−3−(4−(10−メトキシ−3−フェニル−5H−ベンゾ[e]イミダゾ[1,2−c][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(e)トランス−3−アミノ−1−シクロプロピル−3−(4−(9−メトキシ−3−フェニル−5H−ベンゾ[e]イミダゾ[1,2−c][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(f)トランス−3−アミノ−1−シクロプロピル−3−(4−(8−メトキシ−3−フェニル−5H−ベンゾ[e]イミダゾ[1,2−c][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(g)トランス−3−アミノ−1−シクロプロピル−3−(4−(3−フェニル−5H−イミダゾ[1,2−c]ピリド[2,3−e][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(h)トランス−3−アミノ−1−メチル−3−(4−(3−フェニル−5H−イミダゾ[1,2−c]ピリド[2,3−e][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(i)トランス−3−アミノ−1−エチル−3−(4−(3−フェニル−5H−イミダゾ[1,2−c]ピリド[2,3−e][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(j)トランス−3−アミノ−1−シクロプロピル−3−(4−(3−フェニル−5H−イミダゾ[1,2−c]ピリド[3,4−e][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(k)トランス−3−アミノ−1−メチル−3−(4−(3−フェニル−5H−イミダゾ[1,2−c]ピリド[3,4−e] [1,3]オキサジン−2−イル)フェニル)シクロブタノール
(l)トランス−3−アミノ−1−シクロプロピル−3−(4−(3−フェニル−5H−イミダゾ[1,2−c]ピリド[4,3−e][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(m)トランス−3−アミノ−1−メチル−3−(4−(3−フェニル−5H−イミダゾ[1,2−c]ピリド[4,3−e][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(n)トランス−3−アミノ−1−シクロプロピル−3−(4−(3−フェニル−5H−イミダゾ[1,2−c]ピリド[3,2−e][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(o)トランス−3−アミノ−1−シクロプロピル−3−(4−(3−フェニル−5H−イミダゾ[1,2−c]ピラジノゾ[2,3−e][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(p)トランス−3−アミノ−3−(4−(9−(ヒドロキシメチル)−3−フェニル−5H−ベンゾ[e]イミダゾ[1,2−c][1,3]オキサジン−2−イル)フェニル)−1−メチルシクロブタノール
(q)2−(4−(トランス−1−アミノ−3−ヒドロキシ−3−メチルシクロブチル)フェニル)−3−フェニル−5H−ベンゾ[e]イミダゾ[1,2−c][1,3]オキサジン−9−カルボニトリル
(r)トランス−3−アミノ−1−メチル−3−(4−(3−フェニル−9−(1H−ピラゾール−5−イル)−5H−ベンゾ[e]イミダゾ[1,2−c][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(s)2−(4−(トランス−1−アミノ−3−ヒドロキシ−3−メチルシクロブチル)フェニル)−N−メチル−3−フェニル−5H−ベンゾ[e]イミダゾ[1,2−c][1,3]オキサジン−8−カルボキサミド
(t)2−(4−(トランス−1−アミノ−3−ヒドロキシ−3−メチルシクロブチル)フェニル)−N−エトキシ−3−フェニル−5H−ベンゾ[e]イミダゾ[1,2−c][1,3]オキサジン−8−カルボキサミド
〔6〕 PI3K/AKT/mTOR阻害剤が、MK−2206、BEZ235、GDC−0941、Sirolimus、トランス−3−アミノ−1−メチル−3−(4−(3−フェニル−5H−イミダゾ[1,2−c]ピリド[3,4−e] [1,3]オキサジン−2−イル)フェニル)シクロブタノールである〔1〕〜〔5〕のいずれか1項記載の方法。
〔7〕 腫瘍細胞におけるPHLDA1の発現量が予め設定されたカットオフポイント以下であるか、又は腫瘍細胞におけるPIK3C2Bの発現量が予め設定されたカットオフポイント以上であるがん患者を治療するためのPI3K/AKT/mTOR阻害剤を含有する抗腫瘍剤。
〔8〕 PI3K/AKT/mTOR阻害剤を含有する抗腫瘍剤であって、下記工程(1)及び(2)を含む方法により当該抗腫瘍剤を用いた化学療法が十分な治療効果を示す可能性が高いと予測されたがん患者に投与されることを特徴とする抗腫瘍剤。
(2)上記工程(1)で得られたPHLDA1の発現量が予め設定されたカットオフポイント以下の場合、又は上記工程(1)で得られたPIK3C2Bの発現量が予め設定されたカットオフポイント以上の場合、当該がん患者におけるPI3K/AKT/mTOR阻害剤を含有する抗腫瘍剤を用いた化学療法が十分な治療効果を示す可能性が高いと予測する工程。
〔9〕 下記工程(1)及び(2)を含む方法により、がん患者におけるPI3K/AKT/mTOR阻害剤を含有する抗腫瘍剤を用いた化学療法の治療効果を予測するための、PHLDA1及び/又はPIK3C2Bの発現量を測定する試薬を含有するキット:
(1)当該患者から採取された腫瘍細胞を含む生体試料におけるPHLDA1及び/又はPIK3C2Bの発現量を測定する工程、及び
(2)上記工程(1)で得られたPHLDA1の発現量が予め設定されたカットオフポイント以下の場合、又は上記工程(1)で得られたPIK3C2Bの発現量が予め設定されたカットオフポイント以上の場合、当該がん患者におけるPI3K/AKT/mTOR阻害剤を含有する抗腫瘍剤を用いた化学療法が十分な治療効果を示す可能性が高いと予測する工程。
〔10〕 〔1〕〜〔6〕のいずれか1項記載の方法によりPI3K/AKT/mTOR阻害剤を含有する抗腫瘍剤を用いた化学療法が十分な治療効果を示す可能性が高いと予測されたがん患者に、該抗腫瘍剤を投与することを含むがん患者の治療方法。
〔11〕 〔1〕〜〔6〕のいずれか1項記載の方法によりPI3K/AKT/mTOR阻害剤を含有する抗腫瘍剤を用いた化学療法が十分な治療効果を示す可能性が高いと予測されたがん患者の治療に用いるための、PI3K/AKT/mTOR阻害剤を含有する抗腫瘍剤。
〔12〕 がん患者の腫瘍細胞におけるPHLDA1及び/又はPIK3C2Bの発現量に基づき、当該がん患者におけるPI3K/AKT/mTOR阻害剤を含有する抗腫瘍剤を用いた化学療法の治療効果を検査する方法。
〔13〕下記工程(1)及び(2)を含む、〔12〕記載の方法。
(2)上記工程(1)で得られたPHLDA1の発現量が予め設定されたカットオフポイント以下の場合、又は上記工程(1)で得られたPIK3C2Bの発現量が予め設定されたカットオフポイント以上の場合、当該がん患者におけるPI3K/AKT/mTOR阻害剤を含有する抗腫瘍剤を用いた化学療法が十分な治療効果を示す可能性が高いと判定する工程。
本発明における「PI3K/AKT/mTOR阻害剤」とは、PI3K/AKT/mTORシグナルパスウェイにおけるシグナル伝達の亢進を阻害する活性を有する薬剤であれば特に制限されず、PI3K、AKT及びmTORからなる群から選ばれる1あるいは2以上の標的分子に対する阻害剤が挙げられる。好ましくはPI3K阻害剤、AKT阻害剤、mTOR阻害剤又はPI3K−mTORデュアル阻害剤である。なお、これら阻害剤は、PI3K、AKT及びmTOR以外の標的分子に対する阻害活性を併せ持っていても良い。ここで「阻害剤」には、標的分子の活性を阻害する薬剤のみならず、標的分子の発現を阻害する薬剤をも包含する。また、PI3K/AKT/mTOR阻害剤の態様としては、特に制限はなく、低分子化合物、抗体、アンチセンスオリゴヌクレオチド、siRNA及びアプタマー等が挙げられる。
(b)トランス−3−アミノ−1−シクロプロピル−3−(4−(10−フルオロ−3−(ピリジン−4−イル)−5H−ベンゾ[e]イミダゾ[1,2−c][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(c)トランス−3−アミノ−1−シクロプロピル−3−(4−(3−フェニル−5H−ベンゾ[e]イミダゾ[1,2−c][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(d)トランス−3−アミノ−1−シクロプロピル−3−(4−(10−メトキシ−3−フェニル−5H−ベンゾ[e]イミダゾ[1,2−c][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(e)トランス−3−アミノ−1−シクロプロピル−3−(4−(9−メトキシ−3−フェニル−5H−ベンゾ[e]イミダゾ[1,2−c][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(f)トランス−3−アミノ−1−シクロプロピル−3−(4−(8−メトキシ−3−フェニル−5H−ベンゾ[e]イミダゾ[1,2−c][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(g)トランス−3−アミノ−1−シクロプロピル−3−(4−(3−フェニル−5H−イミダゾ[1,2−c]ピリド[2,3−e][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(h)トランス−3−アミノ−1−メチル−3−(4−(3−フェニル−5H−イミダゾ[1,2−c]ピリド[2,3−e][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(i)トランス−3−アミノ−1−エチル−3−(4−(3−フェニル−5H−イミダゾ[1,2−c]ピリド[2,3−e][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(j)トランス−3−アミノ−1−シクロプロピル−3−(4−(3−フェニル−5H−イミダゾ[1,2−c]ピリド[3,4−e][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(k)トランス−3−アミノ−1−メチル−3−(4−(3−フェニル−5H−イミダゾ[1,2−c]ピリド[3,4−e] [1,3]オキサジン−2−イル)フェニル)シクロブタノール(以下、compound−Iと称す。)
(l)トランス−3−アミノ−1−シクロプロピル−3−(4−(3−フェニル−5H−イミダゾ[1,2−c]ピリド[4,3−e][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(m)トランス−3−アミノ−1−メチル−3−(4−(3−フェニル−5H−イミダゾ[1,2−c]ピリド[4,3−e][1,3]オキサジン−2−イル)フェニル)シクロブタノール (n)トランス−3−アミノ−1−シクロプロピル−3−(4−(3−フェニル−5H−イミダゾ[1,2−c]ピリド[3,2−e][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(o)トランス−3−アミノ−1−シクロプロピル−3−(4−(3−フェニル−5H−イミダゾ[1,2−c]ピラジノゾ[2,3−e][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(p)トランス−3−アミノ−3−(4−(9−(ヒドロキシメチル)−3−フェニル−5H−ベンゾ[e]イミダゾ[1,2−c][1,3]オキサジン−2−イル)フェニル)−1−メチルシクロブタノール
(q)2−(4−(トランス−1−アミノ−3−ヒドロキシ−3−メチルシクロブチル)フェニル)−3−フェニル−5H−ベンゾ[e]イミダゾ[1,2−c][1,3]オキサジン−9−カルボニトリル
(r)トランス−3−アミノ−1−メチル−3−(4−(3−フェニル−9−(1H−ピラゾール−5−イル)−5H−ベンゾ[e]イミダゾ[1,2−c][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(s)2−(4−(トランス−1−アミノ−3−ヒドロキシ−3−メチルシクロブチル)フェニル)−N−メチル−3−フェニル−5H−ベンゾ[e]イミダゾ[1,2−c][1,3]オキサジン−8−カルボキサミド
(t)2−(4−(トランス−1−アミノ−3−ヒドロキシ−3−メチルシクロブチル)フェニル)−N−エトキシ−3−フェニル−5H−ベンゾ[e]イミダゾ[1,2−c][1,3]オキサジン−8−カルボキサミド
一般式(I)で表されるイミダゾオキサジン化合物の薬学的に許容される塩としては、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸等の無機酸や、ギ酸、酢酸、プロピオン酸、シュウ酸、マロン酸、コハク酸、フマル酸、マレイン酸、乳酸、リンゴ酸、クエン酸、酒石酸、炭酸、ピクリン酸、メタンスルホン酸、パラトルエンスルホン酸、グルタミン酸などの有機酸との酸付加塩、ナトリウム、カリウム、マグネシウム、カルシウム、アルミニウムなどの無機塩基や、メチルアミン、エチルアミン、メグルミン、エタノールアミンなどの有機塩基、又はリジン、アルギニン、オルニチンなどの塩基性アミノ酸との塩やアンモニウム塩が挙げられる。また、一般式(I)で表されるイミダゾオキサジン化合物には、光学異性体も含まれ、水和物も含まれる。
抗腫瘍剤中に含有されるPI3K/AKT/mTOR阻害剤の量は、これを適用すべき患者の症状により、或いはその剤形等により一定ではないが、一般に投与単位形態あたり、経口剤では約0.05〜1,000mg、注射剤では約0.01〜500mg、坐剤では約1〜1,000mgとするのが望ましい。また、上記投与形態を有する薬剤の1日あたりの投与量は、患者の症状、体重、年齢、性別等によって異なり一概には決定できないが、通常成人(体重50kg)1日あたり約0.05〜5,000mg、好ましくは0.1〜1,000mgとすればよく、これを1日1回又は2〜3回程度に分けて投与するのが好ましい。
[実施例1]
(PHLDA1又はPIK3C2Bの発現量と、PI3K/AKT/mTOR阻害剤に対する感受性との相関)
ヒト乳癌由来37細胞株(AU565、BT20、BT474、BT549、CAMA−1、DU4475、HCC1187、HCC1419、HCC1428、HCC1500、HCC1569、HCC1599、HCC1806、HCC1937、HCC1954、HCC202、HCC2218、HCC38、HCC70、MDA−MB−157、MDA−MB−175、MDA−MB−231、MDA−MB−361、MDA−MB−415、MDA−MB−436、MDA−MB−453、MDA−MB−468、UACC−812、UACC−893(以上、American Type Culture Collection(ATCC)より入手)、MCF−7、SK−BR−3、T47D、ZR−75−1(以上、大日本住友製薬株式会社より入手)、KPL−1、KPL−3C、KPL−4(紅林博士(川崎医大)より供与))を用いて以下のとおり細胞毒性試験を行った。各細胞株は96ウェル平底マイクロプレートに150μL播種し、37℃、5%炭酸ガス含有の培養器中で1日培養した。ジメチルスルホキシドにて段階稀釈したPI3K/AKT/mTOR阻害剤(AKT阻害剤:Compound−I、MK−2206、PI3K−mTORデュアル阻害剤:BEZ235、PI3K阻害剤:GDC−0941、mTOR阻害剤:Sirolimus)及びパクリタキセル、あるいはジメチルスルホキシドのみを各細胞株の培地に添加した。これを先に述べた96ウェル平底マイクロプレートの各ウェルに50μL加えて、薬剤の最終濃度がそれぞれ10000、3000、1000、300、100、30、3、1nMになるようにした。また、別途用意した、各細胞株を一日間培養した96ウェル平底マイクロプレートを室温に30分間放置後、各ウェルから上清を50μLずつ除き、100μLの細胞培養液が残るようにした。残った細胞培養液100μLに対し、等量のCellTiter−Glo Luminescent Cell Viability Assay(Promega、Cat#:G7573)を各ウェルに添加した。10分間暗所で放置した後、マイクロプレートリーダー(PerkinElmer、ARVOsx)にて薬剤添加時のウェルの生細胞由来発光量を測定した。薬剤あるいはジメチルスルホキシドのみを加えた細胞株は37℃、5%炭酸ガス含有の培養器中でさら3日間培養した。培養後、室温に30分間放置し、各ウェルから上清を100μLずつ除き、100μLの細胞培養液が残るようにした。残った細胞培養液100μLに対し、等量のCellTiter−Glo Luminescent Cell Viability Assayを添加した。10分間暗所で放置した後、マイクロプレートリーダーにて各ウェルの生細胞由来発光量を測定した。ヒト乳癌由来37細胞株において、以下の式より細胞増殖率を算出し、細胞増殖率が50%となる濃度、すなわち細胞増殖を50%阻害する各薬剤の濃度(GI50値(μM))を求めた。
細胞増殖率(%)=(T−C0)/C0×100;T<C0の場合
C0:薬剤添加時のウェルの発光量(count per second)
C:ジメチルスルホキシドのみを添加したウェルの発光量(count per second)
T:被検薬剤を添加したウェルの発光量(count per second)
次いで、ヒト乳癌由来37細胞株におけるPHLDA1及びPIK3C2Bの発現量を測定した。各細胞株は、10cm細胞培養ディッシュで50〜80%コンフルエント程度になるまで培養後、RNeasy Mini Kit(QIAGEN、Cat#74106)を用いてマニュアルに従いtotal RNAを抽出した。抽出したtotal RNAは、分光光度計(Nanodrop 1000、Thermo Fisher Scientific)を用いて濃度及び純度を確認した。また、Agilent 2100 Bioanalyzer(Agilent Technologies)を用いて分解度を確認した。GeneChip 3' IVT Express Kit(Affymetrix)を用いて、抽出したtotal RNAをcDNAに逆転写し、さらにビオチン化cRNAへの転写反応を行った。次いで、増幅したビオチン化cRNA(20μg)を断片化した。なお各操作は、キットに添付の説明書の記載に従って行った。得られた各細胞株由来のビオチン化cRNAを検体として、GeneChip Hunman Genome U−133 Plus 2.0 Array(Affymetrix、PIK3C2B probe set ID:204484_at、PHLDA1 probe set ID:217997_at)に添加し、GeneChip Hybridization Oven 640(Affymetrix)に移して、45℃、60rpmの条件下で16時間ハイブリダイゼーションを行った。ハイブリダイゼーション後、GeneChipFluidic Station 450(Affymetrix)を用いて洗浄および蛍光標識を行い、GeneChip Scanner 3000 7G(Affymetrix)を用いてスキャンしてマイクロアレイ・データを取得した。マイクロアレイ・データの解析には、MATLAB(MathWorks)を使用した。遺伝子発現量は、RMA法(Robust Multiarray Average法)により計算した。
(PHLDA1遺伝子ノックダウン、タンパク質の発現量及びリン酸化状態の解析)
PHLDA1遺伝子をノックダウンした場合における、AKTのリン酸化状態を確認することにより、PHLDA1とPI3K/AKT/mTORシグナルパスウェイの関係を検証した。
(PIK3C2B遺伝子ノックダウンによるPI3K/AKT/mTOR阻害剤に対する感受性変化の解析)
ヒト卵巣癌細胞株OVCAR−3(ATCCより入手)は、20% FBS、0.01 mg/mL bovine insulin(Sigma−Aldrich、Cat#I0516)を含むRPMI培地(Life Technologies Corp. 、Cat# A104910−01 )で培養した。ヒト乳癌細胞株HCC1187(ATCCより入手)は、10% FBSを含むRPMI培地(Life Technologies Corp.,Cat# A104910−01)で培養した。
(PI3K/AKT/mTOR阻害剤治療効果予測性における、従来法PIK3CA変異・PTEN欠失測定とPHLDA1・PIK3C2B発現量測定との比較)
臨床において薬効予測マーカーとして検証されているPIK3CA変異あるいはPTEN欠失と、PHLDA1あるいはPIK3C2B発現量について、PI3K/AKT/mTOR阻害剤に対する感受性との相関性の観点から比較した。
Claims (7)
- がん患者から採取した腫瘍細胞におけるPHLDA1及び/又はPIK3C2Bの発現量に基づき、当該がん患者におけるPI3K/AKT/mTOR阻害剤を含有する抗腫瘍剤を用いた化学療法の治療効果を予測する方法であって、
下記工程(1)及び(2)を含み、
(1)当該患者から採取された腫瘍細胞を含む生体試料におけるPHLDA1及び/又はPIK3C2Bの発現量を測定する工程、及び
(2)上記工程(1)で得られたPHLDA1の発現量が予め設定されたカットオフポイント以下である場合、又は上記工程(1)で得られたPIK3C2Bの発現量が予め設定されたカットオフポイント以上である場合、当該がん患者におけるPI3K/AKT/mTOR阻害剤を含有する抗腫瘍剤を用いた化学療法が十分な治療効果を示す可能性が高いと予測する工程、
前記PI3K/AKT/mTOR阻害剤が、一般式(I)
R 1a 、R 1b 、R 1c 、R 1d のうち少なくとも2つが水素原子を示し、他方がそれぞれ
ハロゲン原子、シアノ基、置換基としてヒドロキシル基を有してもよいC1−6アルキル基、C1−6アルコキシ基、置換基としてヒドロキシル基、アミノ基、置換基を有してもよいモノ又はジ(C1−6アルキル)アミノ基又はモノ又はジ(C1−6アルコキシ)アミノ基のいずれかを有するカルボニル基、不飽和複素環基を示し、
R 2 は、フェニル基、ピリジル基、又はチエニル基を示し、
R 3 は、水素原子、メチル基、エチル基、又はシクロプロピル基を示し、
R 4 は、水素原子、又はヒドロキシ基を示す。)
で表されるイミダゾオキサジン化合物又はその薬学的に許容される塩であるか、
AMG−319、AZD−6482、BYL−719、Copanlisib(BAY−80−6946)、GDC−0032、GDC−0084、GSK−1059615 、GSK−2126458、GSK−2636771、Idelalisib(CAL−101)、IPI−145、MLN−1117(INK−1117)、PA−799(CH−5132799)、Pictilisib(GDC−0941)、Pilaralisib(XL−147)、SF−1126、Sonolisib(PX−866) 、Voxtalisib(SAR−245409、XL−765)、Afuresertib hydrochloride(GSK−2110183 )、ARQ−092、AZD5363、Enzastaurin hydrochloride、GDC−0068、GSK−2141795、GSK690693、LY−2780301、MK−2206、Perifosine、Triciribine phosphate(VQD−002)、AZD−2014、AZD−8055、CC−115、CC−223、DS−3078、Everolimus、Temsirolimus、ME−344、MLN−0128(INK−128)、OSI−027、PWT−33597、Ridaforolimus、Sirolimus、Dactolisib(BEZ235) 、DS−7423、GDC−0980、NVP−BGT−226、PF−04691502、PF−05212384(PKI−587)、又はPWT−33597である方法。 - 一般式(I)で表されるイミダゾオキサジン化合物が、A、B、C、及びDは、それぞれC−R1a、C−R1b、C−R1c、及びC−R1dを示すか、或いは前記A、B、C、Dのうちいずれか1又は2つがN原子に置換されていることを示し、
R1a、R1b、R1c、R1dのうち少なくとも2つが水素原子を示し、他方がそれぞれ塩素原子、フッ素原子、シアノ基、メチル基、ヒドロキシメチル基、メトキシ基、エトキシ基、カルボキシル基、カルバモイル基、メチルアミノカルボニル基、エチルアミノカルボニル基、ヒドロキシエチルアミノカルボニル基、エトキシアミノカルボニル基、ピラゾリル基を示し、
R2は、フェニル基、ピリジル基、又はチエニル基を示し、
R3は、水素原子、メチル基、エチル基、又はシクロプロピル基を示し、
R4は、水素原子、又はヒドロキシ基を示す化合物である、請求項1記載の方法。 - 一般式(I)で表されるイミダゾオキサジン化合物が、次の(a)〜(t)のいずれかの化合物である請求項1又は2記載の方法。
(a) トランス−3−アミノ−1−シクロプロピル−3−(4−(10−フルオロ−3−フェニル−5H−ベンゾ[e]イミダゾ[1,2−c][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(b)トランス−3−アミノ−1−シクロプロピル−3−(4−(10−フルオロ−3−(ピリジン−4−イル)−5H−ベンゾ[e]イミダゾ[1,2−c][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(c)トランス−3−アミノ−1−シクロプロピル−3−(4−(3−フェニル−5H−ベンゾ[e]イミダゾ[1,2−c][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(d)トランス−3−アミノ−1−シクロプロピル−3−(4−(10−メトキシ−3−フェニル−5H−ベンゾ[e]イミダゾ[1,2−c][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(e)トランス−3−アミノ−1−シクロプロピル−3−(4−(9−メトキシ−3−フェニル−5H−ベンゾ[e]イミダゾ[1,2−c][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(f)トランス−3−アミノ−1−シクロプロピル−3−(4−(8−メトキシ−3−フェニル−5H−ベンゾ[e]イミダゾ[1,2−c][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(g)トランス−3−アミノ−1−シクロプロピル−3−(4−(3−フェニル−5H−イミダゾ[1,2−c]ピリド[2,3−e][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(h)トランス−3−アミノ−1−メチル−3−(4−(3−フェニル−5H−イミダゾ[1,2−c]ピリド[2,3−e][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(i)トランス−3−アミノ−1−エチル−3−(4−(3−フェニル−5H−イミダゾ[1,2−c]ピリド[2,3−e][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(j)トランス−3−アミノ−1−シクロプロピル−3−(4−(3−フェニル−5H−イミダゾ[1,2−c]ピリド[3,4−e][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(k)トランス−3−アミノ−1−メチル−3−(4−(3−フェニル−5H−イミダゾ[1,2−c]ピリド[3,4−e] [1,3]オキサジン−2−イル)フェニル)シクロブタノール
(l)トランス−3−アミノ−1−シクロプロピル−3−(4−(3−フェニル−5H−イミダゾ[1,2−c]ピリド[4,3−e][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(m)トランス−3−アミノ−1−メチル−3−(4−(3−フェニル−5H−イミダゾ[1,2−c]ピリド[4,3−e][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(n)トランス−3−アミノ−1−シクロプロピル−3−(4−(3−フェニル−5H−イミダゾ[1,2−c]ピリド[3,2−e][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(o)トランス−3−アミノ−1−シクロプロピル−3−(4−(3−フェニル−5H−イミダゾ[1,2−c]ピラジノゾ[2,3−e][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(p)トランス−3−アミノ−3−(4−(9−(ヒドロキシメチル)−3−フェニル−5H−ベンゾ[e]イミダゾ[1,2−c][1,3]オキサジン−2−イル)フェニル)−1−メチルシクロブタノール
(q)2−(4−(トランス−1−アミノ−3−ヒドロキシ−3−メチルシクロブチル)フェニル)−3−フェニル−5H−ベンゾ[e]イミダゾ[1,2−c][1,3]オキサジン−9−カルボニトリル
(r)トランス−3−アミノ−1−メチル−3−(4−(3−フェニル−9−(1H−ピラゾール−5−イル)−5H−ベンゾ[e]イミダゾ[1,2−c][1,3]オキサジン−2−イル)フェニル)シクロブタノール
(s)2−(4−(トランス−1−アミノ−3−ヒドロキシ−3−メチルシクロブチル)フェニル)−N−メチル−3−フェニル−5H−ベンゾ[e]イミダゾ[1,2−c][1,3]オキサジン−8−カルボキサミド
(t)2−(4−(トランス−1−アミノ−3−ヒドロキシ−3−メチルシクロブチル)フェニル)−N−エトキシ−3−フェニル−5H−ベンゾ[e]イミダゾ[1,2−c][1,3]オキサジン−8−カルボキサミド - PI3K/AKT/mTOR阻害剤が、MK−2206、BEZ235、GDC−0941、Sirolimus、トランス−3−アミノ−1−メチル−3−(4−(3−フェニル−5H−イミダゾ[1,2−c]ピリド[3,4−e] [1,3]オキサジン−2−イル)フェニル)シクロブタノールである請求項1〜3のいずれか1項記載の方法。
- PI3K/AKT/mTOR阻害剤が、AKT阻害剤又はmTOR阻害剤である請求項1〜4のいずれか1項記載の方法。
- 前記PHLDA1の発現量のカットオフポイントは、PHLDA1の低発現群と高発現群を切り分けるカットオフポイントであって、PHLDA1の低発現群と高発現群の治療効果におけるログランク検定でP値が最小となる値又はP値がある水準未満になる値である請求項1に記載の方法。
- 下記工程(1)及び(2)を含む方法により、がん患者におけるPI3K/AKT/mTOR阻害剤を含有する抗腫瘍剤を用いた化学療法の治療効果を予測するための、PHLDA1及び/又はPIK3C2Bの発現量を測定する試薬を含有するキット:
(1)当該患者から採取された腫瘍細胞を含む生体試料におけるPHLDA1及び/又はPIK3C2Bの発現量を測定する工程、及び
(2)上記工程(1)で得られたPHLDA1の発現量が予め設定されたカットオフポイント以下の場合、又は上記工程(1)で得られたPIK3C2Bの発現量が予め設定されたカットオフポイント以上の場合、当該がん患者におけるPI3K/AKT/mTOR阻害剤を含有する抗腫瘍剤を用いた化学療法が十分な治療効果を示す可能性が高いと予測する工程、
前記PI3K/AKT/mTOR阻害剤が、一般式(I)
R 1a 、R 1b 、R 1c 、R 1d のうち少なくとも2つが水素原子を示し、他方がそれぞれ
ハロゲン原子、シアノ基、置換基としてヒドロキシル基を有してもよいC1−6アルキル基、C1−6アルコキシ基、置換基としてヒドロキシル基、アミノ基、置換基を有してもよいモノ又はジ(C1−6アルキル)アミノ基又はモノ又はジ(C1−6アルコキシ)アミノ基のいずれかを有するカルボニル基、不飽和複素環基を示し、
R 2 は、フェニル基、ピリジル基、又はチエニル基を示し、
R 3 は、水素原子、メチル基、エチル基、又はシクロプロピル基を示し、
R 4 は、水素原子、又はヒドロキシ基を示す。)
で表されるイミダゾオキサジン化合物又はその薬学的に許容される塩であるか、
AMG−319、AZD−6482、BYL−719、Copanlisib(BAY−80−6946)、GDC−0032、GDC−0084、GSK−1059615 、GSK−2126458、GSK−2636771、Idelalisib(CAL−101)、IPI−145、MLN−1117(INK−1117)、PA−799(CH−5132799)、Pictilisib(GDC−0941)、Pilaralisib(XL−147)、SF−1126、Sonolisib(PX−866) 、Voxtalisib(SAR−245409、XL−765)、Afuresertib hydrochloride(GSK−2110183 )、ARQ−092、AZD5363、Enzastaurin hydrochloride、GDC−0068、GSK−2141795、GSK690693、LY−2780301、MK−2206、Perifosine、Triciribine phosphate(VQD−002)、AZD−2014、AZD−8055、CC−115、CC−223、DS−3078、Everolimus、Temsirolimus、ME−344、MLN−0128(INK−128)、OSI−027、PWT−33597、Ridaforolimus、Sirolimus、Dactolisib(BEZ235) 、DS−7423、GDC−0980、NVP−BGT−226、PF−04691502、PF−05212384(PKI−587)、又はPWT−33597であるキット。
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US8193182B2 (en) | 2008-01-04 | 2012-06-05 | Intellikine, Inc. | Substituted isoquinolin-1(2H)-ones, and methods of use thereof |
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US8828998B2 (en) | 2012-06-25 | 2014-09-09 | Infinity Pharmaceuticals, Inc. | Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors |
JP6084291B2 (ja) | 2013-07-18 | 2017-02-22 | 大鵬薬品工業株式会社 | Fgfr阻害剤の間歇投与用抗腫瘍剤 |
WO2015008844A1 (ja) | 2013-07-18 | 2015-01-22 | 大鵬薬品工業株式会社 | Fgfr阻害剤耐性癌の治療薬 |
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