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Targeting cholecystokinin-2 receptor for pancreatic cancer chemoprevention

Altaf Mohammed1, Naveena B Janakiram2, Chen Suen1

  • 1Division of Cancer Prevention, Chemoprevention Agent Development Research Group, National Cancer Institute, Bethesda, Maryland.

Molecular Carcinogenesis
|July 18, 2019
PubMed

Insights

CCK2R antagonists JNJ-26070109 and YF476 reduced pancreatic ductal adenocarcinoma (PDAC) progression in mice. JNJ-26070109 demonstrated superior chemopreventive efficacy, though gender-specific effects warrant careful dosing considerations.

Area of Science:

  • Oncology
  • Gastroenterology
  • Pharmacology

Background:

  • Gastrin signaling via cholecystokinin-2 receptor (CCK2R) is implicated in pancreatic cancer.
  • CCK2R antagonists are potential therapeutic agents for pancreatic ductal adenocarcinoma (PDAC).

Purpose of the Study:

  • To evaluate the chemopreventive effects of CCK2R antagonists YF476 and JNJ-26070109 on PDAC progression in a genetically engineered mouse model.
  • To compare the efficacy of JNJ-26070109 and YF476 in preventing PDAC development.

Main Methods:

  • Genetically engineered mice (p48Cre/+; LSL-KrasG12D) were treated with varying doses of JNJ-26070109 or YF476 for 38 weeks.
  • Pancreatic intraepithelial neoplasia (PanIN) and PDAC incidence were assessed.
  • Transcriptome analysis was performed to identify gene expression changes.

Main Results:

  • Both JNJ-26070109 and YF476 significantly inhibited PDAC incidence in male mice.
  • JNJ-26070109 showed higher efficacy, particularly in male mice, with dose-dependent effects.
  • Gender-specific responses were observed, with varying efficacy in female mice.
  • Transcriptome analysis revealed distinct gene expression patterns associated with each antagonist treatment.

Conclusions:

  • JNJ-26070109 exhibits superior chemopreventive efficacy against PDAC progression compared to YF476 in this mouse model.
  • The study highlights the potential of CCK2R antagonists in PDAC chemoprevention.
  • Gender-specific effects necessitate careful dose selection and further investigation.
Keywords:
CCK2Rchemopreventionkraspancreatic cancer

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