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Purpose: Anatomical and molecular staging strategies are needed for the personalized treatment of localized pancreatic ductal adenocarcinoma (PDAC). This study evaluated the performance of [68 Ga]Ga–FAPI-04 and [18F]F-FDG PET/CT on the disease staging and prognostic value of patients with localized PDAC on contrast-enhanced (CE)-CT images. Methods: Patients with suspected localized PDAC on CE-CT were recruited for static [68 Ga]Ga-FAPI-04 and 18[F]F-FDG and PET/CT, and select patients underwent simultaneous 60-min dynamic 68 Ga-FAPI-04 PET/CT. The diagnostic and staging performances of the static PET/CT results were evaluated by delineating regions of interest in the primary tumor, whole pancreas, and distal pancreas in both types of scans and then evaluating correlations between the PET/CT findings and clinicopathological characteristics. Furthermore, Kaplan–Meier and hazard ratio (log-rank) methods were used to evaluate the prognostic value of the combined dynamic [68 Ga]Ga-FAPI-04 and static [18F]F-FDG PET/CT method. Results: We included 49 patients with histologically confirmed PDAC adenocarcinomas; 32 underwent 60-min dynamic [68 Ga]Ga-FAPI-04 PET/CT imaging simultaneously. The static [68 Ga]Ga-FAPI-04 method had significantly higher accuracy and uptake values than the static [18F]F-FDG method for primary PDAC lesions, metastatic lymph nodes, and distal metastases. Furthermore, 18.4% and 10.2% of the patients' stages changed after using the [68 Ga]Ga-FAPI-04 and [18F]F-FDG PET/CT methodologies, respectively, compared to the CE-CT-designated stage. The Ki values obtained from dynamic [68 Ga]Ga-FAPI-04 PET/CT did not differ between PDAC and distal obstructive pancreatitis lesions. Pathologically enlarged tumor size, poor differentiation, and perineural invasion were associated with increased [68 Ga]Ga-FAPI-04 uptake but not with [18F]F-FDG uptake. The preoperative prognostic performance of [68 Ga]Ga-FAPI-04 was better than that of [18F]F-FDG. Interestingly, combined [68 Ga]Ga-FAPI-04 and [18F]F-FDG uptake results in the whole pancreas could further stratify patients based on their postoperative prognosis. Conclusion: 6[68 Ga]Ga-FAPI-04 PET/CT was more sensitive and accurate than [18F]F-FDG PET/CT for tumor, node, and metastasis staging of PDAC identified on CE-CT. Additionally, [68 Ga]Ga-FAPI-04 uptake was significantly associated with pathologically aggressive tumor features. Combined [68 Ga]Ga-FAPI-04 and [18F]F-FDG PET/CT findings improved the prognostic value, potentially providing a non-invasive guide for clinical management. Finally, increased fibroblast activity in PDAC-induced obstructive pancreatitis may be associated with poor patient survival rates. [ABSTRACT FROM AUTHOR]

Purpose: Our aim was to assess the prognostic value of [68 Ga]Ga-FAPI-04 positron emission tomography (PET) uptake in PDAC and to evaluate the correlation between in vivo lesional radioactivity with pathological characteristics of pancreatic ductal adenocarcinoma (PDAC). Methods: We retrospectively analyzed treatment‐naïve PDAC patients who underwent preoperative [68 Ga]Ga-FAPI-04 PET/CT followed by pancreatectomy. The tracer uptake was determined as maximum tumor standardized uptake value (SUVmax), FAPI-avid tumor volume (FTV), total lesion FAP expression (TLF) as well total pancreatic uptake (TSUVmax), total FAPI-avid pancreatic volume (FPV), and total pancreatic FAP expression (TPF). Spearman's correlation analysis was performed to evaluate the association between [68 Ga]Ga-FAPI-04 PET/CT imaging and ex vivo immunohistological FAP expression and pathological characteristics of surgical specimens (differentiation, size, vascularity, perineural invasion, and lymph node metastases). Kaplan–Meier and hazard ratio (HR, log-rank) methods were used to evaluate the prognostic value of [68 Ga]Ga-FAPI-04 PET/CT and clinicopathological factors. Results: Thirty-seven surgical PDAC patients were included. The ex vivo expression of FAP was significantly associated with the tumor SUVmax and TLF. FAP expression was more abundant in poorly differentiated PDAC than in well- to moderately differentiated neoplasms. Tumor SUVmax or TLF and pancreatic TSUVmax or TPF were significantly correlated with tumor size, differentiation, and perineural invasion, respectively. SUVmax had a significant independent prognostic value for recurrence-free survival (HR = 2.46, P < 0.05), while [68 Ga]Ga-FAPI-04 TPF predicted overall survival (HR = 12.82, P < 0.05). Conclusion: The in vivo [68 Ga]Ga-FAPI-04 uptake in localized PDAC showed a significant correlation with ex vivo FAP expression and aggressive pathological characteristics. [68 Ga]Ga-FAPI-04 PET/CT also presented a potential for postoperative prognostication of PDAC. Elevated fibroblast activity induced by obstructive pancreatitis might be associated with the patient's survival. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic malignancy for which there are currently no effective anti-metastatic therapies. Herein, we employed single-cell RNA sequencing and metabolomics analysis to demonstrate that metastatic cells highly express focal adhesion kinase (FAK), which promotes metastasis by remodeling choline kinase α (CHKα)-dependent choline metabolism. We designed a novel CHKα inhibitor, CHKI-03, and verified its efficacy in inhibiting metastasis in multiple preclinical models. Classical and newly synthesized small-molecule inhibitors have previously been used to assess the therapeutic potential of targeting mTOR and CHKα in various animal models. Mechanistically, FAK activated mTOR and its downstream HIF-1α, thereby elevating CHKα expression and promoting the proliferation, migration, and invasion of PDAC cells, as well as tumor growth and metastasis. Consistently, high expression levels of both FAK and CHKα are correlated with poor prognosis in patients with PDAC. Notably, CHK1-03 inhibited CHKα expression and also suppressed mTORC1 phosphorylation, disrupting the mTORC1-CHKα positive feedback loop. In addition, the combination of CHKI-03 and the mTORC1 inhibitor rapamycin synergistically inhibited tumor growth and metastasis in PDX models. The combination of CHKI-03 and rapamycin demonstrates considerable therapeutic efficacy in PDO models resistant to gemcitabine. Our findings reveal a pivotal mechanism underlying PDAC metastasis regulated by mTORC1-CHKα loop-dependent choline metabolism reprogramming, highlighting the therapeutic potential of this novel regimen for treating PDAC metastasis. • PDAC cells highly express FAK, which promotes metastasis by altering choline metabolism dependent on CHKα. • A new CHKα inhibitor, CHKI-03, demonstrates potential in inhibiting both proliferation and metastasis of PDAC in laboratory and animal models. • CHKI-03 suppresses CHKα activation and inhibits mTORC1 phosphorylation, disrupting an mTORC1-CHKα positive feedback loop. • Combined targeting of mTOR and CHKα shows promising therapeutic efficacy in pancreatic cancer patients with liver metastases, as observed in PDO and PDX models. [ABSTRACT FROM AUTHOR]