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A PET Imaging Strategy for Interrogating Target Engagement and Oncogene Status in Pancreatic Cancer.

A PET Imaging Strategy for Interrogating Target Engagement and Oncogene Status in Pancreatic Cancer.

Authors :
Henry KE
Dacek MM
Dilling TR
Caen JD
Fox IL
Evans MJ
Lewis JS
Source :
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.
Publication Year :
2019

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.<br />Experimental Design: In this study, we aimed to test whether zirconium-89 transferrin ([ <superscript>89</superscript> 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.<br />Results: Mice bearing iKras*p53* tumors showed significantly higher ( P < 0.05) uptake of [ <superscript>89</superscript> Zr]Zr-Tf in mice withdrawn from inducible oncogenic KRAS. A therapy study with JQ1 showed a statistically significant decrease ( P < 0.05) of [ <superscript>89</superscript> 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.<br />Conclusions: Our study demonstrates that [ <superscript>89</superscript> 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.<br /> (©2018 American Association for Cancer Research.)

Details

Language :
English
ISSN :
1557-3265
Volume :
25
Issue :
1
Database :
MEDLINE
Journal :
Clinical cancer research : an official journal of the American Association for Cancer Research
Publication Type :
Academic Journal
Accession number :
30228208
Full Text :
https://doi.org/10.1158/1078-0432.CCR-18-1485