Pancreatic ductal adenocarcinoma (PDAC) is one of the most common causes of cancer related death. Despite the advances in understanding of the molecular pathogenesis, pancreatic cancer remains a major unsolved health problem. Overall, the 5-year survival rate is less than 5% demonstrating the insufficiency of current therapies.Most cytotoxic therapies induce apoptosis and PDAC cells have evolved a plethora of molecular mechanisms to assure survival. We will present anti-apoptotic strategies working at the level of the death receptors, the mitochondria or involving the caspase inhibitors of the IAP family. Furthermore, the survival function of the phosphotidylinositol-3' kinase (PI3K)/AKT-and NFkappaB-pathways are illustrated. A detailed molecular knowledge of the anti-apoptotic mechanisms of PDAC cells will help to improve therapies for this dismal disease and therapeutic strategies targeting the programmed cell death machinery are in early preclinical and clinical development.

Introduction: Fibroblast activation protein (FAP) is overexpressed in several solid tumors and therefore represents an attractive target for radiotheranostic applications. Recent investigations demonstrated rapid and high uptake of small-molecule inhibitors of FAP ( 68 Ga-FAPI-46) for PET imaging. Here, we report our initial experience in terms of feasibility and safety of 90 Y-labelled FAPI-46 ( 90 Y-FAPI-46) for radioligand therapy (RLT) of extensively pretreated patients with solid tumors. Methods: Patients were considered for 90 Y-FAPI-46 therapy in case of (a) exhaustion of all approved therapies based on multidisciplinary tumor board decision and (b) high FAP expression, defined as SUVmax ≥ 10 in more than 50% of all lesions. If tolerated, posttherapeutic 90 Y-FAPI-46 bremsstrahlung scintigraphy was performed to visually confirm systemic distribution and focal tumor uptake, and 90 Y-FAPI-46 PET scans at multiple timepoints were performed to determine absorbed dose. Blood-based dosimetry was used to determine bone-marrow absorbed dose. Adverse Events were graded using CTCAE v.5.0. Results: Nine patients with either metastatic soft tissue or bone sarcoma (N = 6) and pancreatic cancer (N = 3) were treated between June 2020 and March 2021. Patients received a median of 3.8 (IQR 3.25-5.40) GBq for the first cycle and three patients received subsequent cycles with a median of 7.4 (IQR 7.3-7-5) GBq. Post-therapy 90 Y-FAPI-46 bremsstrahlung scintigraphy demonstrated sufficient 90 Y-FAPI-46 uptake in tumor lesions in 7 of 9 patients (78%). Mean absorbed dose was 0.52 Gy/GBq (IQR 0.41-0.65) in kidney, 0.04 Gy/GBq (IQR 0.03-0.06) in bone marrow and below 0.26 Gy/GBq in the lung and liver. Measured tumor lesions received up to 2.28 Gy/GBq (median 1.28Gy/GBq). Hematologic G3/G4 toxicities were noted in four patients (44%), of which

The phosphoinositide-3-kinase (PI3K)/AKT signaling pathway controls fundamental processes of cancer cell biology like proliferation and cell survival. The PI3K/AKT pathway is activated in pancreatic ductal adenocarcinoma (PDAC) cells. The molecular mechanisms linking PI3K signaling to the cell cycle machinery in PDAC cells are not investigated in detail. Using the PI3K inhibitor Ly294002 as well as small interfering RNA targeting AKT1 expression, we show that PI3K controls the proliferation and G 1 phase progression of PDAC cells. Gene profiling revealed several important regulators of G 1 -S phase progression controlled by PI3K signaling like p21Cip1 , S-phase kinase-associated protein 2 (SKP2), CDC25a, cyclin A, cyclin D2, CDK2, and cyclin E. We show that the F-box protein SKP2, an oncogene up-regulated in PDAC, is transcriptionally regulated by the PI3K/AKT1 pathway in PDAC cells. At the molecular level, the control of the SKP2 gene by PI3K is due to the regulation of E2F1 binding to the proximal SKP2 gene promoter. The complex and profound connection of PI3K/ AKT1 signaling to the cell cycle qualifies this pathway as a suitable target for therapeutic intervention in PDAC. [Cancer Res 2007;67(9):4149-56]

Hepatocellular cancers arise in a background of liver damage and inflammation. Bakiri et al. describe the function of the transcription factor c-Fos/AP-1 using mouse models and human data. c-Fos affects cholesterol and bile acid metabolism and induces DNA damage and inflammation, thus promoting liver cancer.

Introduction: Bone and soft tissue sarcomas express fibroblast activation protein (FAP) on tumor cells and associated fibroblast. Therefore, FAP is a promising therapeutic and diagnostic target.Novel radio-labelled FAP-Inhibitors (e.g. 68 Ga-FAPI46) have shown high tumor uptake in positron emission tomography (PET) in sarcoma patients. Here we report endpoints of the FAPI-PET prospective observational trial.Methods: Forty-seven patients with bone or soft tissue sarcomas undergoing clinical 68 Ga-FAPI-PET were eligible for enrollment into the FAPI-PET observational trial. Of these patients, 43 patients also underwent 18 F-Fluordesoxyglucose PET (FDG). The primary study endpoint was the association of 68 Ga-FAPI-PET uptake intensity and histopathological FAP-expression analyzed with Spearman's r correlation. Secondary endpoints were detection rate, positive predictive value (PPV), interreader reproducibility, and change in management. Datasets were interpreted by two blinded readers.Results: Primary endpoint was met and the association between FAPI-PET uptake intensity and histopathological FAP-expression was significant (Spearman's r = 0.43; p = 0.03). By histopathological validation PPV was 1.00 (95% CI, 0.87-1.00) on a per-patient and 0.97 (95% CI, 0.84-1.00) on a per-region basis. In cases with histopathologic validation, 27 of 28 (96%) confirmed patients and 32 of 34 (94%) confirmed regions were PET positive resulting in an SE of 0.96 (95%CI, 0.82-1.00) on a per-patient and 0.94 (95%CI, 0.80-0.99) on a per-region basis. The detection rate on a per-patient basis in FAPI-and FDG-PET was 76.6% and 81.4%, respectively.In 8 (18.6%) patients FAPI-PET resulted in an upstaging compared to FDG-PET. FAPI-PET readers showed substantial to almost perfect agreement for the defined regions (Fleiss kappa: primary κ = 0.78; local nodal κ = 0.54; distant nodal κ = 0.91; lung κ = 0.86; bone κ = 0.69 and other κ = 0.65). Clinical management changed in 13 (30%) patients after FAPI-PET. Conclusion:We confirm an association of tumoral FAPI-PET uptake intensity and histopathological FAP expression in sarcoma patients. Further, using blinded reads and independent histopathological validation we report high PPV and sensitivity of FAPI-PET for sarcoma staging.

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Introduction Positron emission tomography (PET) using small ligands of the fibroblast activation protein (FAP) was recently introduced. However, optimal uptake time has not been defined yet. Here, we systematically compare early (~ 10 min p.i.) and late (~ 60 min p.i.) FAPI-46 imaging in patients with various types of cancer. Methods This is a retrospective single-institutional study. Imaging was performed at the Essen University Hospital, Germany. A total of 69 patients who underwent dual time-point imaging for either restaging (n = 52, 75%) or staging (n = 17, 25%) of cancer were included. Patients underwent PET with two acquisitions: early (mean 11 min, SD 4) and late (mean 66 min, SD 9). Mean injected activity was 148 MBq (SD 33). Results In total, 400 lesions were detected in 69 patients. Two of 400 (0.5%) lesions were only seen in early time-point imaging but not in late time-point imaging. On a per-patient level, there was no significant difference between SUVmax of hottest tumor lesions (Wilcoxon: P = 0.73). Organ uptake demonstrated significant early to late decrease in SUVmean (average ∆SUVmean: − 0.48, − 0.14, − 0.27 for gluteus, liver, and mediastinum, respectively; Wilcoxon: P < 0.001). On a per-lesion basis, a slight increase of SUVmax was observed (average ∆SUVmax: + 0.4, Wilcoxon: P = 0.03). Conclusion In conclusion, early (~ 10 min p.i.) versus late (~ 60 min p.i.) FAPI-46 imaging resulted in equivalent lesion uptake and tumor detection. For improved feasibility and scan volume, we implement early FAPI-46 PET in future clinical and research protocols.

Understanding the molecular pathogenesis of inflammatory liver disease is essential to design efficient therapeutic approaches. In hepatocytes, the dimeric transcription factor c-JUN/AP-1 is a major mediator of cell survival during hepatitis, although functions for other JUN proteins in liver disease are less defined. Here, we found that JUNB was specifically expressed in human and murine immune cells during acute liver injury. We analyzed the molecular function of JUNB in experimental models of hepatitis, including administration of concanavalin A (ConA) or α-galactosyl-ceramide, which induce liver inflammation and injury.