A PET Imaging Strategy for Interrogating Target Engagement and Oncogene Status in Pancreatic Cancer.
| Autor: | Henry KE; Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York., Dacek MM; Program of Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York.; Department of Pharmacology, Weill Cornell Medical College, New York, New York., Dilling TR; Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York., Caen JD; Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York., Fox IL; Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York., Evans MJ; Departments of Radiology and Biomedical Imaging, and Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California., Lewis JS; Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York. lewisj2@mskcc.org.; Program of Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York.; Department of Pharmacology, Weill Cornell Medical College, New York, New York.; Department of Radiology, Weill Cornell Medical College, New York, New York.; Radiochemistry and Molecular Imaging Probes Core, Memorial Sloan Kettering Cancer Center, New York, New York. |
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| Jazyk: | angličtina |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2019 Jan 01; Vol. 25 (1), pp. 166-176. Date of Electronic Publication: 2018 Sep 18. |
| DOI: | 10.1158/1078-0432.CCR-18-1485 |
| Abstrakt: | 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 ([ 89 Zr]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 [ 89 Zr]Zr-Tf in mice withdrawn from inducible oncogenic KRAS. A therapy study with JQ1 showed a statistically significant decrease ( P < 0.05) of [ 89 Zr]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 [ 89 Zr]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. (©2018 American Association for Cancer Research.) |
| Databáze: | MEDLINE |
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