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研究分野生物医学と臨床科学腫瘍学とがん発生分子標的
臓がんにおけるRAS- GTP抑制の腫瘍選択的活性

臓がんにおけるRAS- GTP抑制の腫瘍選択的活性

Urszula N Wasko ^1,2, Jingjing Jiang ³, Tanner C Dalton ^1,2, Alvaro Curiel-Garcia ^1,2, A Cole Edwards ⁴, Yingyun Wang ³, Bianca Lee ³, Margo Orlen ⁵, Sha Tian ⁶, Clint A Stalnecker ^7,8, Kristina Drizyte-Miller ⁷, Marie Menard ³, Julien Dilly ^9,10, Stephen A Sastra ^1,2, Carmine F Palermo ^1,2, Marie C Hasselluhn ^1,2, Amanda R Decker-Farrell ^1,2, Stephanie Chang ³, Lingyan Jiang ³, Xing Wei ³, Yu C Yang ³, Ciara Helland ³, Haley Courtney ³, Yevgeniy Gindin ³, Karl Muonio ³, Ruiping Zhao ³, Samantha B Kemp ⁵, Cynthia Clendenin ¹¹, Rina Sor ¹¹, William P Vostrejs ⁵, Priya S Hibshman ⁴, Amber M Amparo ⁷, Connor Hennessey ^9,10, Matthew G Rees ¹², Melissa M Ronan ¹², Jennifer A Roth ¹², Jens Brodbeck ³, Lorenzo Tomassoni ^2,13, Basil Bakir ^1,2, Nicholas D Socci ¹⁴, Laura E Herring ¹⁵, Natalie K Barker ¹⁵, Junning Wang ^9,10, James M Cleary ^9,10, Brian M Wolpin ^9,10, John A Chabot ¹⁶, Michael D Kluger ¹⁶, Gulam A Manji ^1,2, Kenneth Y Tsai ^17,18, Miroslav Sekulic ¹⁹, Stephen M Lagana ¹⁹, Andrea Califano ^{1,2,13,20,21,22,23,24}, Elsa Quintana ³, Zhengping Wang ³, Jacqueline A M Smith ³, Matthew Holderfield ³, David Wildes ³, Scott W Lowe ^6,25, Michael A Badgley ^1,2, Andrew J Aguirre ^9,10,12,26, Robert H Vonderheide ^5,11,27, Ben Z Stanger ^5,11, Timour Baslan ²⁸, Channing J Der ^7,8, Mallika Singh ²⁹, Kenneth P Olive ^30,31

Urszula N Wasko ^1,2, Jingjing Jiang ³, Tanner C Dalton ^1,2

¹Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
²Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.
³Revolution Medicines, Redwood City, CA, USA.
⁴Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵University of Pennsylvania Perelman School of Medicine, Department of Medicine, Philadelphia, PA, USA.
⁶Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁷Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁸Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁰Harvard Medical School, Boston, MA, USA.
¹¹University of Pennsylvania Perelman School of Medicine, Abramson Cancer Center, Philadelphia, PA, USA.
¹²The Broad Institute of Harvard and MIT, Cambridge, MA, USA.
¹³Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA.
¹⁴Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁵UNC Michael Hooker Proteomics Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁶Department of Surgery, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
¹⁷Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
¹⁸Department of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
¹⁹Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
²⁰Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
²¹J. P. Sulzberger Columbia Genome Center, Columbia University, New York, NY, USA.
²²Department of Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center, New York, NY, USA.
²³Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY, USA.
²⁴Chan Zuckerberg Biohub New York, New York, NY, USA.
²⁵Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
²⁶Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
²⁷Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
²⁸Department of Biomedical Sciences, School of Veterinary Medicine, The University of Pennsylvania, Philadelphia, PA, USA.
²⁹Revolution Medicines, Redwood City, CA, USA. msingh@revmed.com.
³⁰Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA. kenolive@columbia.edu.
³¹Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA. kenolive@columbia.edu.

⁰Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.

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2024年4月8日

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まとめ

この要約は機械生成です。

RMC-7977による広範なRAS阻害は,臓管内腺癌のモデルにおいて有意な抗腫瘍活性を示した. 組み合わせた治療は抵抗性のメカニズムを克服し有望な治療戦略を提示します

科学分野

腫瘍学
分子生物学
薬物の発見

背景

RAS変異はヒトの癌の約4分の1を引き起こします
管腺癌 (PDAC) はしばしばKRAS変異によって引き起こされる (> 90%).
RASをターゲットにすることで様々な癌の治療戦略が生まれます

研究の目的

選択的RAS- GTP阻害剤であるRMC-7977の治療の可能性を臨床前モデルで評価する.
PDACにおけるRMC-7977の抗腫瘍活性と耐性を調査する.
耐性メカニズムと潜在的な組み合わせ治療を特定する.

主な方法

様々なPDACモデルにおけるRMC-7977の in vitroおよびin vivo評価
腫瘍と正常な組織に対する薬物効果の薬理学的分析.
KPCマウスモデルにおける生存延長と抵抗メカニズムの評価
耐性を克服するために TEAD 結合抑制の in vitro 試験

主要な成果

RMC-7977は,PDACモデルにおいて,広範囲で強力な抗腫瘍活性を示し,in vivoでは良好な耐受性を示した.
腫瘍はアポトーシスと持続的な増殖停止を示したが,正常な組織はアポトーシスなしで一時的な効果を示した.
RMC-7977治療は,KPCマウスモデルで生存期間を大幅に延長し,再発が続いた.
Myc複製数の増加は,組合せ TEAD 阻害に反応する抵抗メカニズムとして特定されました.

結論

広範囲のRAS- GTP阻害はPDAC治療の有望な戦略である.
RMC-7977は,PDACモデルにおいて,臨床前における有意な抗腫瘍効果を示している.
TEADの結合抑制は,RMC-7977に対する抵抗を克服する有効な戦略です.

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