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  • [Clin Cancer Res.] 췌장암 종양유전자상태를 PET으로 평가A PET Imaging Strategy for Interrogating Target Engagement and Oncogene Status in Pancreatic Cancer.

    Memorial Sloan Kettering Cancer Center / Lewis JS*

  • 출처
    Clin Cancer Res.
  • 등재일
    2019 Jan 1
  • 저널이슈번호
    25(1):166-176. doi: 10.1158/1078-0432.CCR-18-1485. Epub 2018 Sep 18.
  • 내용

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    Abstract
    PURPOSE:
    Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers, with a 5-year survival rate of less than 10%. Physicians often rely on biopsy or CT to guide treatment decisions, but these techniques fail to reliably measure the actions of therapeutic agents in PDAC. KRAS mutations are present in >90% of PDAC and are connected to many signaling pathways through its oncogenic cascade, including extracellular regulated kinase (ERK) and MYC. A key downstream event of MYC is transferrin receptor (TfR), which has been identified as a biomarker for cancer therapeutics and imaging.

    EXPERIMENTAL DESIGN:
    In this study, we aimed to test whether zirconium-89 transferrin ([89Zr]Zr-Tf) could measure changes in MYC depending on KRAS status of PDAC, and assess target engagement of anti-MYC and anti-ERK-targeted therapies.

    RESULTS:
    Mice bearing iKras*p53* tumors showed significantly higher (P < 0.05) uptake of [89Zr]Zr-Tf in mice withdrawn from inducible oncogenic KRAS. A therapy study with JQ1 showed a statistically significant decrease (P < 0.05) of [89Zr]Zr-Tf uptake in drug versus vehicle-treated mice bearing Capan-2 and Suit-2 xenografts. IHC analysis of resected PDAC tumors reflects the data observed via PET imaging and radiotracer biodistribution.

    CONCLUSIONS:
    Our study demonstrates that [89Zr]Zr-Tf is a valuable tool to noninvasively assess oncogene status and target engagement of small-molecule inhibitors downstream of oncogenic KRAS, allowing a quantitative assessment of drug delivery.

     


    Author information

    Henry KE1, Dacek MM2,3, Dilling TR1, Caen JD1, Fox IL1, Evans MJ4, Lewis JS5,2,3,6,7.
    1
    Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
    2
    Program of Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York.
    3
    Department of Pharmacology, Weill Cornell Medical College, New York, New York.
    4
    Departments of Radiology and Biomedical Imaging, and Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California.
    5
    Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York. lewisj2@mskcc.org.
    6
    Department of Radiology, Weill Cornell Medical College, New York, New York.
    7
    Radiochemistry and Molecular Imaging Probes Core, Memorial Sloan Kettering Cancer Center, New York, New York.

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