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

Kelly E Henry1, Megan M Dacek2,3, Thomas R Dilling1

  • 1Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|September 20, 2018
PubMed
Abstract

Insights

Zirconium-89 transferrin ([89Zr]Zr-Tf) PET imaging can noninvasively assess KRAS oncogene status and drug target engagement in pancreatic ductal adenocarcinoma (PDAC) models, aiding therapeutic assessment.

Area of Science:

  • Oncology
  • Molecular Imaging
  • Cancer Therapeutics

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with limited treatment monitoring tools.
  • KRAS mutations drive PDAC, activating signaling pathways like ERK and MYC.
  • Transferrin receptor (TfR) is a biomarker for cancer therapeutics and imaging, downstream of MYC.

Purpose of the Study:

  • To evaluate [89Zr]Zr-Tf as a PET imaging agent to measure MYC changes related to KRAS status in PDAC.
  • To assess target engagement of anti-MYC and anti-ERK therapies using [89Zr]Zr-Tf.

Main Methods:

  • PET imaging with [89Zr]Zr-Tf in mouse models of PDAC with varying KRAS status.
  • Therapy studies using JQ1 (an anti-MYC agent) in PDAC xenografts.
  • Immunohistochemistry (IHC) analysis of resected tumors.

Main Results:

  • [89Zr]Zr-Tf uptake was significantly higher in tumors with withdrawn oncogenic KRAS.
  • JQ1 treatment led to a significant decrease in [89Zr]Zr-Tf uptake in xenografts.
  • PET imaging data correlated with IHC findings.

Conclusions:

  • [89Zr]Zr-Tf is a valuable tool for noninvasive assessment of oncogene status in PDAC.
  • This radiotracer enables quantitative evaluation of drug delivery and target engagement for KRAS-pathway inhibitors.

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