JP6970709B2 - Rasがんにおける脂質捕捉 - Google Patents
Rasがんにおける脂質捕捉 Download PDFInfo
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- JP6970709B2 JP6970709B2 JP2019097670A JP2019097670A JP6970709B2 JP 6970709 B2 JP6970709 B2 JP 6970709B2 JP 2019097670 A JP2019097670 A JP 2019097670A JP 2019097670 A JP2019097670 A JP 2019097670A JP 6970709 B2 JP6970709 B2 JP 6970709B2
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Description
本発明は、国立衛生研究所により授与された助成金番号CA163591の下、政府支援により成された。政府は、本発明に一定の権利を有する。
がん細胞は、増殖を支持するために一定のエネルギー供給および構造的な構成成分を必要とする。多くのがん細胞は、高いde novo脂質合成速度を有することが示されている(例えば、Santos & Schulze FEBS J MiniReview 279巻(15号):2610頁、2012年7月3日参照)。近年、がんを処置するために、いくつかの治療開発戦略が、脂質生合成の阻害剤に焦点を合わせている。
上述の観察は、Ras駆動性がんの処置に有用な組成物および製剤が絶えず必要であるという証拠となる。
本開示は、具体的には、低酸素状態の細胞が、血清脂肪酸を捕捉することによってde
novo脂質生成を迂回し、したがってアセチル−CoAの必要性および酸素依存性SCD1−反応の両方を迂回するという認識、さらにはde novo脂質生成の低酸素状態による再プログラミングが、酸素正常状態の細胞においてRas活性化によって再生され得るという認識を包含する。したがって本開示は、例えばRas駆動性腫瘍を含めたRas駆動性細胞が、SCD1阻害に耐性を示し得ることを実証する。さらに本開示は、例えばRas駆動性腫瘍を含めたRas駆動性細胞が、それらによる脂質捕捉の成功を低減する治療レジメンに対して感受性を示し得ることを実証する。
本発明の実施形態において、例えば以下の項目が提供される。
(項目1)
Ras関連腫瘍による脂質捕捉を阻害することによって、Ras関連がんを処置する方法。
(項目2)
環境からの好適な捕捉脂質を制限することを含む、項目1に記載の方法。
(項目3)
前記好適な捕捉脂質が、多価不飽和脂質であるか、またはそれを含む、項目2に記載の方法。
(項目4)
前記好適な捕捉脂質が、リン脂質であるか、またはそれを含む、項目2に記載の方法。
(項目5)
前記好適な捕捉脂質が、リゾリン脂質であるか、またはそれを含む、項目3に記載の方法。
(項目6)
前記好適な捕捉脂質が、ホスファチジルグリセロール脂質であるか、またはそれを含む、項目2に記載の方法。
(項目7)
前記好適な捕捉脂質が、より高い不飽和度の脂肪酸であるか、またはそれを含む、項目2に記載の方法。
(項目8)
前記好適な捕捉脂質が、より長い炭素鎖であるか、またはそれを含む、項目2に記載の方法。
(項目9)
腫瘍関連性Ras変異体タンパク質、該変異体をコードする核酸および/または相補的な核酸の存在またはレベルを検出することによって、脂質生合成阻害剤を用いる治療に対する応答性の見込みに基づき腫瘍を分類する方法。
(項目10)
脂質捕捉に対する薬剤の効果を、適切な対照と比較して決定することによって、がんの処置に有用な薬剤を同定し、かつ/または特徴付ける方法。
(項目11)
脂質捕捉を阻害するステップが、食事による脂質摂取を制御することを含む、項目1に記載の方法。
(項目12)
過剰の完全飽和した脂肪酸が消費されるように、食事による脂質摂取が制御される、項目11に記載の方法。
(項目13)
多価不飽和脂肪酸に対する飽和脂肪酸の比が、2、3、4、5、8、10、15、20、25、30、35、40、45、または50を超えるように、食事による脂質摂取が制御される、項目11に記載の方法。
(項目14)
多価不飽和脂肪酸に対する飽和脂肪酸の比が、2、3、4、5、8、10、15、20、25、30、35、40、45、または50を超えるように、食事による脂質摂取が制御される、項目11に記載の方法。
(項目15)
0.3重量%未満の必須脂肪酸を含む脂肪酸を含む、栄養サプリメント。
(項目16)
0.1重量%未満の濃度のアラキドン酸を含む、項目15に記載の栄養サプリメント。
(項目17)
前記栄養サプリメントの少なくとも70重量%が脂質である、項目15に記載の栄養サプリメント。
(項目18)
前記脂質が、動物源および/または植物源に由来する、項目15に記載の栄養サプリメント。
(項目19)
前記脂質が、ココナツに由来する、項目18に記載の栄養サプリメント。
(項目20)
前記脂質が、陸生動物源または酪農源に由来する、項目18に記載の栄養サプリメント。
(項目21)
タンパク質源をさらに含む、項目15に記載の栄養サプリメント。
(項目22)
炭水化物源をさらに含む、項目15に記載の栄養サプリメント。
(項目23)
丸剤またはカプセル剤の形態である、項目15に記載の栄養サプリメント。
(項目24)
がんを処置する方法であって、過剰の飽和脂肪酸を含む治療食を、がんの処置を必要としている患者に投与することを含む方法。
(項目25)
前記過剰が、多価不飽和脂肪酸に対して1を超える飽和脂肪酸の比からなるか、またはその比を含む、項目24に記載の方法。
(項目26)
多価不飽和脂肪酸に対する飽和脂肪酸の前記比が、2、3、4、5、8、10、15、20、25、30、35、40、45、または50を超える、項目24に記載の方法。
(項目27)
前記がんが、Ras関連がんである、項目24に記載の方法。
(項目28)
前記Ras駆動がんが、膵臓がん、非小細胞肺がん、結腸直腸がん、膀胱がん、腎臓がん、甲状腺がん、黒色腫、肝細胞癌、および血液系悪性腫瘍からなる群から選択される、項目27に記載の方法。
(項目29)
前記治療食が、少なくとも2週間にわたって投与される、項目24に記載の方法。
(項目30)
前記治療食が、3週間、4週間、5週間、6週間、7週間、8週間、9週間、10週間、11週間、12週間、13週間、14週間、15週間、16週間、17週間、18週間、19週間、20週間、21週間、22週間、23週間、24週間、25週間、26週間の期間にわたって、または治療エンドポイントが観察されるまで投与される、項目29に記載の方法。
(項目31)
前記飽和脂肪酸が、動物源および/または植物源に由来する、項目24に記載の方法。
(項目32)
前記飽和脂肪酸が、ココナツに由来する、項目31に記載の方法。
(項目33)
前記飽和脂肪酸が、陸生動物源または酪農源に由来する、項目31に記載の方法。
(項目34)
化学療法剤を投与することをさらに含む、項目24に記載の方法。
(項目35)
がんを処置する方法であって、がん細胞成長の1種または複数の薬理学的阻害剤を、がんの処置を必要としている患者に投与することと、該患者に、多価不飽和脂肪酸に対して1を超える比の飽和脂肪酸を含む治療食を消費するように指示することとを含む、方法。
(項目36)
化学療法を投与することをさらに含む、項目1に記載の方法。
(項目37)
がんを処置する方法であって、がん細胞成長の1種または複数の薬理学的阻害剤を、がんの処置を必要としている患者に投与することと、該患者に、項目15に記載の栄養サプリメントを含む治療食を消費するように指示することとを含む、方法。
活性化剤:本明細書で使用される場合、用語「活性化剤」は、その存在またはレベルが、薬剤が存在しない状態(または異なるレベルの薬剤が存在する状態)で観察される標的のレベルまたは活性と比較して、標的のレベルまたは活性の上昇と相関する薬剤を指す。一部の実施形態では、活性化剤は、その存在またはレベルが、特定の参照レベルまたは活性(例えば公知の活性化剤、例えば陽性対照が存在するなどの適切な参照条件下で観察されるもの)と比較できるまたはそれを超える標的レベルまたは活性と相関する薬剤である。
がんにおける脂質代謝
がん細胞は、それらの増殖を支持するために一定のエネルギー供給および構造的な構成成分を必要とする。癌遺伝子は、代謝を活発に再プログラムして、この供給を容易にする(1、2)。ヒトのがんにおいて最も一般的に活性化される経路の2つが、PI3K−Akt経路およびRas経路である(3)。PI3K−Akt経路は、がんにおいて役割を果たすことに加えて、インスリンシグナル伝達の主なエフェクターであるため、この経路の代謝効果は広範囲に研究されてきた。Akt活性化は、グルコースの取込み、解糖フラックス、および乳酸排出、すなわちワールブルグ効果を促進する(2)。さらに、Akt活性化は、mTORの下流活性化によって、タンパク質合成を増加させる(4)。最後にAktは、酵素リン酸化、およびSREBPのmTOR依存性活性化のような転写活性化を含めた機序を介して、脂質生成を誘導する(5、6)。
novo脂肪酸合成および不飽和化の要求が減少することを見出した。発癌性Rasは、低酸素状態の代謝表現型を繰り返し、脂肪酸取込みへの依存度が増加すると、Ras駆動性がん細胞はSCD1阻害に耐性を有するようになる。移入脂肪酸の主な供給源は、1つの脂肪酸の尾部を有する血清脂質であるリゾ脂質である。単一の脂肪酸の尾部を有する脂質を異化する能力は、侵襲性のがんおよびRas駆動性がんにおいて増強されることが以前に示された(26〜28)。本発明の結果は、関係するリゾ脂質の捕捉が、低酸素状態の細胞およびRas駆動性がん細胞の両方における脂肪酸獲得の主な経路であり得ることを示している。
本開示は、特に、例えばRas関連腫瘍などの腫瘍細胞における脂質捕捉を標的化するための様々な技術の価値を実証し、それを提供する。一部の実施形態では、このような標的化は、それらの環境から脂質を上手く捕捉する細胞(例えば、腫瘍細胞)および/または腫瘍の同定を可能にする。一部の実施形態では、提供される技術によって、脂質捕捉の度合いおよび/もしくは種類、ならびに/または脂質生合成と比較した場合の脂質捕捉への相対的な依存を同定し、かつ/または特徴付けることができる。したがって、このような技術は、脂質捕捉系を改変することによって成長、増殖および/または生存率が影響を受け得る細胞および/または腫瘍の同定を可能にする。
とりわけ、本開示は、ある特定のRas関連腫瘍が脂質捕捉を利用し、かつ/またはそれに依存することを実証する。したがって本発明によれば、このような腫瘍は、脂質生合成を阻害または妨害する治療様式に応答する可能性が相対的に低く、脂質捕捉を阻害または妨害する治療様式に応答する可能性が相対的に高いようである。
原則として、レベル、形態および/または活性が、脂質捕捉の特色と相関し、かつ/またはそれをモジュレートする(例えば阻害するまたは増強する)任意の薬剤は、少なくとも本明細書に記載のある特定の実施形態では、脂質捕捉を標的化する薬剤であり得る。
一部の実施形態では、本開示は、脂質捕捉を標的化する薬剤の同定および/または特徴付けのための方法論を提示する。
本明細書に記載の通り、本発明は、例えば脂質生合成を標的化する治療または脂質捕捉を標的化する治療などの特定のタイプの治療に応答する可能性が高いまたは低い腫瘍を検出および/または分類するための様々な方法論を提供する。
哺乳動物細胞の成長は、膜構造の複製を必要とする。このことに基づいて、脂肪酸シンターゼおよびアセチルCoAカルボキシラーゼを含めた脂肪酸シンターゼ酵素の阻害剤を用いたがんの処置に関心が集まっている。このような酵素は、「非必須」脂肪酸を生成する。しかし、脂質構造物の複製は、オメガ−3脂肪酸およびオメガ−6脂肪酸などの多価不飽和脂肪酸を含めた必須脂肪酸も必要とする。
とりわけ、本開示は、食事による脂肪酸摂取をモジュレートすることによって、ある特定の腫瘍を処置することを包含する。
一部の実施形態では、本明細書に記載の通り脂質捕捉を標的化する様式は、がん、例えばRas関連がんの処置における1つまたは複数の他の治療と組み合わされる。
本発明の方法の様々な実施形態によれば、食事レジメンまたはサプリメントの一部として摂取するための、脂質捕捉を標的化する薬剤および/または脂質は、被験体に単独で、または本明細書に記載の通り組成物もしくは医薬の構成成分として投与することができる。一部の実施形態では、提供される薬剤または脂質は、医薬組成物を調製するための生理的に許容される担体または賦形剤を用いて製剤化することができる。一部の実施形態では、このような医薬組成物に利用される担体および/または組成物は、それら自体が無菌であり得る。一部の実施形態では、医薬組成物は、特定の投与モードに合わせて製剤化される。組成物を製剤化する方法は、当技術分野で公知である(例えば、Remington’s Pharmaceuticals Sciences、第17版、Mack Publishing Co.、(Alfonso R. Gennaro編)(1989年)参照)。
(実施例1)
低酸素状態の細胞およびRas形質転換細胞は、リゾリン脂質由来の不飽和脂肪酸を捕捉することによって成長を支持する
材料および方法
細胞の脂肪酸源を、13C−標識グルコースおよび13C−標識グルタミンで確かめることができる。哺乳動物細胞は、取込みまたはde novo合成のいずれかによって脂肪酸を獲得する(図1A)。脂肪酸シンターゼによって飽和脂肪酸であるパルミチン酸(C16:0)が生成され、それが不飽和化および/または伸長されると、多様な脂肪酸を生じることができる。このような脂肪酸への代謝経路は、13C−標識グルコースおよび13C−標識グルタミン(アセチル−CoAを標識化するため)を均一に供給し、その後けん化された脂肪酸を質量分析にかけることによって確かめることができる。パルミチン酸については、このような分析により、血清由来の脂肪酸ならびにde novo脂質生成から生じた標識化形態の移入に起因して、非標識化分率(M0ピーク)が明らかになる。これらの標識化形態には、U−13C−パルミチン酸(M+16)、および不完全なアセチル−CoAの標識化に起因して生じる部分的に標識化された形態が含まれ(図1B)、相対的に豊富な部分的および完全に標識化された形態は、細胞質アセチル−CoAの標識化分率を決定するのに十分である。この手法を、多様な起源を有する5種類のがん細胞系に適用することによって、過去の知見と一致して、酸素正常状態では、de novo脂質生成が細胞のC16:0プールの75〜90%を占めることが実証される(図1C)(30)。
LC18:1=(D)(LC18:0)(方程式1)
D=LcellC18:1/LcellC18:0(方程式2)
vitroおよび異種移植の両方で、がん細胞の成長を阻止することができる。しかし、A549肺がん細胞を用いる実験では、C18:1標識化を完全に阻止した(図4A)SCD1阻害剤の用量(200nMのCAY10566)は、リアルタイムの細胞増殖アッセイ(10%血清、図4B)において、または標準細胞培養条件における成長の最初の48時間、細胞成長は損なわれなかった(図S3)。血清脂質によって支持された持続的細胞成長と一致して、2%血清に切り替えると、細胞はSCD1阻害に対して感受性になった(図4B)。A549細胞は、発癌性K−Rasを自然に発現し、RasはC18:1の取込みを促進するので、構成的なRas活性化は、SCD1阻害に対する耐性を誘導する可能性があると仮定された。このことを調査するために、SCD1阻害剤の存在下で、H−RasV12GまたはmyrAktを有するiBMK細胞を成長させた。阻害剤は、両方の細胞株においてSCD1を完全に阻止した(図S4)。それにもかかわらず、10%血清では、myrAkt細胞の成長が著しく損なわれた一方、H−RasV12G細胞は、ほぼ普通に集団倍加数3で成長した(図4C、図S3)。再びこれらのデータによって、本明細書で実証された通り、脂肪酸代謝を標的化する治療様式、特にSCD1を標的化する治療様式が、他のがん(例えば、AKt関連腫瘍)を処置するために使用される場合には有用および/または有効とあり得るとしても、ある特定のRas関連腫瘍の処置に関して、有効でない可能性があること、少なくとも単独では有効でない可能性があることが確認される。
培地(10%血清)における全脂肪酸および遊離(非エステル化)脂肪酸の濃度、ならびにA549細胞およびiBMK−H−RASV12G細胞における脂肪酸の総濃度。培地の遊離脂肪酸は、培地の全脂肪酸の5%未満を構成する。
腫瘍は、それらの細胞膜を複製し、それによって成長するために脂肪酸を必要とする。がん細胞は、それらの非必須脂肪酸の大部分をde novo合成することが一般に想定される。この想定は、主に、10%血清および酸素正常状態で実施された細胞培養実験に基づくものである。この想定は、最も重要な発癌経路の1つであるPI3K−Akt−mTORのグルコース依存性の脂質生成促進効果によって裏付けられる。また、RasはAktを活性化するので(3、36)、グルコース依存性の脂質生成促進の役割を有している可能性があると考えられている。
良性の隣接組織と比較した膵臓の腫瘍組織の脂肪酸含量
本発明の実施例は、膵管腺癌腫瘍および良性の隣接組織のペア試料における脂質の存在量の分析を記載する。
食事管理の効果
本発明の実施例は、Ras関連腫瘍の成長に対するある特定の食事プログラムの効果を実証する。
Claims (23)
- Ras駆動性がん細胞または低酸素の細胞の成長を阻害する方法において使用するための栄養サプリメントであって、不飽和脂肪酸に対して過剰な飽和脂肪酸を含み、
該方法は、Ras駆動性がんまたは低酸素状態を有する被験体に該栄養サプリメントを提供することを含み、かつ、該方法は、対照と比べて、Ras駆動性がん細胞または低酸素の細胞によるリゾ脂質取込みを低減させることを含む、栄養サプリメント。 - 前記リゾ脂質が1つまたは複数のリゾリン脂質を含む、請求項1に記載の栄養サプリメント。
- 前記リゾ脂質が1つまたは複数のリゾホスファチジルコリン脂質を含む、請求項1または2に記載の栄養サプリメント。
- 前記リゾホスファチジルコリン脂質が、LPC(18:0)脂質である、請求項3に記載の栄養サプリメント。
- 取込みを低減させることが、細胞環境から利用可能なリゾ脂質の量を低減させることを含む、請求項1〜4のいずれか一項に記載の栄養サプリメント。
- 前記利用可能なリゾ脂質の量を低減させることが、前記細胞からリゾ脂質を実質的に枯渇させることを含む、請求項1〜5のいずれか一項に記載の栄養サプリメント。
- 前記リゾ脂質の各々が、1つまたは複数のオメガ−6脂肪酸の尾部を含む、請求項1〜6のいずれか一項に記載の栄養サプリメント。
- 前記栄養サプリメントが、多価不飽和脂肪酸を実質的に含まない、請求項1〜7のいずれか一項に記載の栄養サプリメント。
- 前記栄養サプリメントが、0.1重量%未満のアラキドン酸を含む、請求項1〜8のいずれか一項に記載の栄養サプリメント。
- 前記不飽和脂肪酸が、グリセロリン脂質を含む、請求項1〜9のいずれか一項に記載の栄養サプリメント。
- 前記細胞が低酸素の細胞である、請求項1〜10のいずれか一項に記載の栄養サプリメント。
- 前記細胞ががん細胞である、請求項1〜11のいずれか一項に記載の栄養サプリメント。
- 前記細胞が膵臓がん細胞である、請求項1〜12のいずれか一項に記載の栄養サプリメント。
- 前記細胞が肺がん細胞である、請求項1〜12のいずれか一項に記載の栄養サプリメント。
- 前記不飽和脂肪酸が、1つまたは複数のオメガ−3脂肪酸を含む、請求項1〜14のいずれか一項に記載の栄養サプリメント。
- 前記栄養サプリメントが1つまたは複数の飽和脂肪酸の尾部を含む1つまたは複数の脂質を含む、請求項1〜15のいずれか一項に記載の栄養サプリメント。
- 前記1つまたは複数の脂質の各々が、複数の脂肪酸の尾部を含む、請求項16に記載の栄養サプリメント。
- 前記1つまたは複数の脂質が、2つの脂肪酸の尾部を持つホスファチジルコリン脂質である、請求項16または17に記載の栄養サプリメント。
- 前記ホスファチジルコリン脂質が、PC(16:0,18:1)脂質である、請求項18に記載の栄養サプリメント。
- 前記1つまたは複数の脂質が飽和リゾ脂質である、請求項16〜19のいずれか一項に記載の栄養サプリメント。
- 前記飽和リゾ脂質が、LPC(18:0)脂質である、請求項20に記載の栄養サプリメント。
- 前記不飽和脂肪酸が多価不飽和脂肪酸を含み、前記栄養サプリメントが少なくとも10:1または少なくとも30:1の比の飽和脂肪酸:多価不飽和脂肪酸を含む、請求項1〜21のいずれか一項に記載の栄養サプリメント。
- 前記不飽和脂肪酸が多価不飽和脂肪酸を含み、前記栄養サプリメントが少なくとも50:1の比の飽和脂肪酸:多価不飽和脂肪酸を含む、請求項1〜22のいずれか一項に記載の栄養サプリメント。
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