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Dimeric CCK2R radiotheranostic tracers synergize with mTOR inhibition for enhanced tumor therapy

Linjie Bian1,2,3,4, Zheyi Wang5,6, Panli Li1,2,3,4

  • 1Department of Nuclear Medicine, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, shanghai 200032, China.

Theranostics
|September 18, 2025
PubMed

Insights

A novel dimeric radiotracer targeting the cholecystokinin-2 receptor (CCK2R) shows improved tumor targeting and retention. Combining this agent with mTOR inhibition enhances radiotherapy efficacy for CCK2R-positive cancers.

Area of Science:

  • Nuclear Medicine
  • Oncology
  • Molecular Imaging

Background:

  • The cholecystokinin-2 receptor (CCK2R) is a key target in neuroendocrine cancers like medullary thyroid carcinoma and small cell lung cancer.
  • Existing minigastrin analogs show promise for CCK2R-targeted radiotheranostics.

Purpose of the Study:

  • To develop and evaluate a novel dimeric CCK2R-targeted radiotracer, DOTA-CCK2R-dimer.
  • To investigate the radiosensitization potential of this agent in combination with mTOR inhibition.

Main Methods:

  • Design and synthesis of DOTA-CCK2R-dimer.
  • Labeling with Gallium-68 (68Ga) for PET imaging and Lutetium-177 (177Lu) for therapy.
  • In vivo tumor targeting assessment and comparison with monomeric tracer.
  • Combination therapy with RAD001 (mTOR inhibitor).
  • Single-cell RNA sequencing (scRNA-seq) to elucidate radiosensitization mechanisms.

Main Results:

  • DOTA-CCK2R-dimer demonstrated superior in vivo tumor targeting and retention compared to its monomeric counterpart.
  • [177Lu]Lu-DOTA-CCK2R-dimer selectively eliminated proliferative and poorly differentiated tumor cells.
  • Combination therapy suppressed glutathione-mediated detoxification and increased oxidative stress.
  • Glutathione S-transferase kappa 1 (GSTK1) was identified as a key regulator of radiosensitivity.

Conclusions:

  • DOTA-CCK2R-dimer offers excellent in vivo stability, tumor retention, and imaging performance for CCK2R-positive malignancies.
  • Combination with mTOR inhibition presents a synergistic strategy to sensitize tumors to radiotherapy.
  • This approach holds promise for treating refractory CCK2R-positive cancers.
Keywords:
Multimeric radioligandNeuroendocrine tumorsOxidative stress modulationPeptide receptor radionuclide therapy (PRRT)Radiosensitization

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