The Cholecystokinin-B Receptor as a Candidate Diagnostic Biomarker and Translational Target for Precision Oncology in Pancreatic Cancer

Background/Objectives: Identification of cell-surface receptors on cancer tissues that are absent in the corresponding normal tissue provide an opportunity for target-specific diagnostics and drug delivery. The cholecystokinin-B receptor (CCKBR) was initially overlooked as a high-priority biomarker for pancreatic cancer (PDAC) because comparisons were made between cancer and “normal adjacent tissue” from The Cancer Genome Atlas (TCGA). Since PDAC is highly invasive and significantly alters the tumor microenvironment, we now know the adjacent tissue is not normal in PDAC. Methods: A multi-cohort transcriptomic analysis was conducted to evaluate the true expression landscape of CCKBR in human pancreatic tissue. Bulk RNA-sequencing data were harmonized from the Genotype-Tissue Expression (GTEx) repository (N = 328) with true normal pancreas samples and TCGA Pancreatic Adenocarcinoma cohort (N = 178) primary tumors. Confirmation of CCKBR protein expression was performed using a human tissue array. The significance of a single-nucleotide polymorphism (SNP, rs1800843) that results in CCKBR mis-splicing was characterized. A biodegradable fluorescent polyplex nanoparticle (NP) was developed to selectively target the CCKBR and was tested using p48-Cre/LSL-KrasG12D (KC) mice. Results: CCKBR transcripts exhibited a profound, binary-like upregulation in malignant tissue compared to normal tissue, achieving statistical significance (p = 10−60). The germline SNP of the CCKBR (rs1800843) was identified in ~40% of patients with confirmed PDAC. Immunoreactivity for the CCKBR protein was absent in normal human pancreas but increased in precancerous PanIN lesions and cancer. A fluorescent labeled CCKBR-targeted NP revealed uptake in the pancreas of KC mice and localized to the PanIN lesions. Conclusions: These data provide new insights into CCKBR, supporting its potential as a diagnostic biomarker and a therapeutic target in precision pancreatic oncology.