A PET imaging strategy for interrogating target engagement and oncogene status in pancreatic cancer Journal Article

Authors: Henry, K. E.; Dacek, M. M.; Dilling, T. R.; Caen, J. D.; Fox, I. L.; Evans, M. J.; Lewis, J. S.
Article Title: A PET imaging strategy for interrogating target engagement and oncogene status in pancreatic cancer
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 iKrasp53 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 0.05) uptake of [89Zr]Zr-Tf in mice withdrawn from inducible oncogenic KRAS.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. © 2018 American Association for Cancer Research.
Journal Title: Clinical Cancer Research
Volume: 25
Issue: 1
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2019-01-01
Start Page: 166
End Page: 176
Language: English
DOI: 10.1158/1078-0432.Ccr-18-1485
PUBMED: 30228208
PROVIDER: scopus
PMCID: PMC6320277
Notes: Article -- Export Date: 1 February 2019 -- Source: Scopus
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MSK Authors
  1. Jason S Lewis
    239 Lewis
  2. Kelly Elizabeth Henry
    5 Henry
  3. Megan Dacek
    2 Dacek
  4. Jonathan David Caen
    1 Caen
  5. Ian Lubroth Fox
    1 Fox