Back to Search
Start Over
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.
- 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 Zr]Zr-Tf in mice withdrawn from inducible oncogenic KRAS.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.)
- Subjects :
- Adenocarcinoma diagnostic imaging
Adenocarcinoma genetics
Adenocarcinoma pathology
Animals
Carcinoma, Pancreatic Ductal diagnostic imaging
Carcinoma, Pancreatic Ductal genetics
Carcinoma, Pancreatic Ductal pathology
Cell Line, Tumor
Cell Proliferation drug effects
Gene Expression Regulation, Neoplastic
Heterografts
Humans
Mice
Mitogen-Activated Protein Kinase 3 antagonists & inhibitors
Mitogen-Activated Protein Kinase 3 genetics
Molecular Targeted Therapy
Proto-Oncogene Proteins c-myc antagonists & inhibitors
Proto-Oncogene Proteins c-myc genetics
Radioisotopes chemistry
Radioisotopes pharmacology
Signal Transduction drug effects
Transferrin chemistry
Transferrin pharmacology
Zirconium chemistry
Zirconium pharmacology
Adenocarcinoma drug therapy
Carcinoma, Pancreatic Ductal drug therapy
Positron-Emission Tomography
Proto-Oncogene Proteins p21(ras) genetics
Subjects
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