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18F-FLT PET, a Noninvasive Pharmacodynamic Biomarker of Tumor Cell Proliferation, Detected Differential Response to

Anand Giddabasappa1, Ziyue Karen Jiang1, Bing Yang1

  • 1Animal Models and Imaging, Comparative Medicine-Drug Safety R&D, Pfizer Inc., San Diego, California.

Molecular Cancer Therapeutics
|March 21, 2025
PubMed

Insights

18F-FLT PET imaging effectively measures cell proliferation and differentiates treatment efficacy for cyclin-dependent kinase (CDK) inhibitors. This non-invasive biomarker shows potential for identifying patient response in CDK inhibitor clinical trials, especially concerning Palbociclib resistance.

Area of Science:

  • Oncology
  • Molecular Imaging
  • Pharmacodynamics

Background:

  • Dysregulated cell cycle is a cancer hallmark; cyclin-dependent kinase (CDK) inhibition is a key therapeutic strategy.
  • 18F-FLT (18F-3'-deoxy-3'-fluorothymidine) positron emission tomography (PET) is a validated biomarker for measuring cell proliferation.

Purpose of the Study:

  • To evaluate 18F-FLT PET imaging as a pharmacodynamic (PD) biomarker for assessing the efficacy of PF-07104091 (a CDK2 selective inhibitor).
  • To differentiate treatment response in models sensitive or resistant to Palbociclib (a CDK4/6 inhibitor) and other CDK inhibitors.

Main Methods:

  • 18F-FLT PET imaging was performed after 4 days of CDK inhibitor treatment.
  • Tumor growth inhibition (TGI) studies were conducted.
  • Immunohistochemistry (IHC) biomarkers (Ki67 and pRb) were evaluated for correlation with PET imaging.

Main Results:

  • 18F-FLT PET differentiated Palbociclib resistance from sensitivity to PF-06873600 (CDK2/4/6 inhibitor) and PF-07104091 in the OVCAR-3 model.
  • PF-07104091 demonstrated dose-dependent TGI and reduced 18F-FLT uptake in both MCF7 and OVCAR-3 models, and an ovarian cancer PDX model.
  • IHC biomarkers (Ki67, pRb) correlated with 18F-FLT uptake trends across all models.

Conclusions:

  • 18F-FLT PET serves as a quantitative, non-invasive, whole-body biomarker for assessing CDK inhibitor efficacy.
  • 18F-FLT PET imaging can identify patients responding or not responding to CDK inhibitors, particularly in cases of Palbociclib resistance.
  • This imaging modality holds potential for use in novel CDK inhibitor clinical trials.

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