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BBO-10203は,RAS- PI3Kαの相互作用を阻害することによって,高血糖を引き起こすことなく腫瘍の成長を抑制する

Dhirendra K Simanshu¹, Rui Xu², James P Stice²

¹NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, USA.

Science (New York, N.Y.)

|June 12, 2025

まとめ

BBO-10203は,前臨床モデルにおいて腫瘍を有意に抑制する,フォスホイノシチド3キナーゼα (PI3Kα) を標的とする新しい経口薬である. このPI3Kα阻害剤は,高血糖を引き起こすことなく,腫瘍の成長を効果的に抑制します.

科学分野:

腫瘍学
分子生物学
薬理学について

背景:

フォスホイノシチド3キナーゼα (PI3Kα) は,様々な癌に関与する重要なシグナル伝達酵素である.
RAS媒介によるPI3Kαの活性化は,腫瘍の発達と進行において重要な役割を果たします.
PIK3CA,KRAS,およびHER2の増幅/過剰発現における腫瘍性突然変異は,複数の腫瘍型において一般的な要因である.

研究の目的:

経口投与可能なPI3Kα阻害剤であるBBO-10203の有効性を臨床前がんモデルで評価する.
BBO-10203の作用機構を調査し,PI3KαのRAS結合領域への特定の結合に焦点を当てた.
BBO-10203の単独療法および他の標的薬との併用における可能性を評価する.

主な方法:

BBO- 10203は,臨床前がんモデルで経口投与された.
PI3Kα活性化の阻害は,特定の腫瘍変異または増幅を有する腫瘍で評価された.
KEAP1およびSTK11変異を含む様々な腫瘍の成長抑制を評価した.
併用療法には,CDK4/ 6,ER,HER2,KRAS- G12Cの阻害剤が含まれていた.

主要な成果:

BBO-10203は,PI3KαのRAS結合ドメインに結合し,RASタンパク質による活性化を防ぐ.
この薬は,腫瘍性KRAS,PIK3CA変異,またはHER2増幅/過剰発現を有する腫瘍においてPI3Kα抑制を示した.
多種多様な腫瘍において,有意な腫瘍増殖抑制が観察された.
特にKEAP1およびSTK11変異を有する腫瘍において,併用療法において有効性の向上が認められた.

結論:

BBO-10203は,臨床前モデルにおける広範な抗腫瘍活性を持つ強力なPI3Kα阻害剤である.
CDK4/ 6,ER,HER2,KRAS- G12C阻害剤を含む他の標的療法と併用すると,薬剤の有効性が強化されます.
BBO-10203は高血糖を引き起こすことなく抗腫瘍効果を達成し,明確な治療窓を示唆しています.

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