Antidepressant regulation of PDAC

Project Summary: Pancreatic ductal adenocarcinoma (PDAC) has a dismal survival rate due to its late-stage diagnosis, propensity to metastasize, and the paucity of effective anti-tumor therapies that can eradicate metastatic disease. PDAC develops a dense fibrosis, is characterized by pro-tumor immunity and intense perineural invasion (PNI). Antifibrotic therapies have yielded mixed and often disappointing clinical results, while immune treatments for PDAC have been severely compromised by the dense stroma, lack of infiltrating CD8 T cells and hypoxia. There remains a paucity of information regarding factors that regulate PNI in PDAC, poor insight into how it modulates metastasis, and a lack of clinically tractable treatments to reduce PDAC PNI. Interestingly, a high percentage of Americans receive antidepressants for a variety of reasons, which accumulating data suggest may exert additional off target anti-tumor effects. Our preliminary clinical data revealed tricyclic antidepressants (TCA) and selective serotonin reuptake inhibitors (SSRIs) reduce PDAC incidence and enhance patient outcome. Our preclinical studies in genetically engineered mouse models (GEMMs) of PDAC showed TCAs inhibit metastasis, reduce fibrosis and PNI, and improve anti-tumor immunity; at least in part by decreasing the activity of acid ceramidases (aCDase). This has led us to hypothesize that Antidepressants inhibit PDAC metastasis and may improve treatment response by decreasing aCDase activity to reduce tissue fibrosis and PNI and improve antitumor immunity. To test this prediction, we have assembled a multidisciplinary team of basic, computational and clinical scientists at UCSF with expertise in PDAC, the extracellular matrix; PNI, tumor immunology, epidemiology/bioinformatics, drug development and design, and pathology. Together we will 1. Determine if antidepressants (TCA, SSRIs) inhibit PDAC metastasis by reducing fibrosis, PNI and inflammation, 2. Test whether antidepressants (TCA, SSRIs) prevent PDAC metastasis by reducing aCDase activity to inhibit fibrosis, PNI and inflammation, and 3. Explore clinical relevance and potential impact of antidepressant treatment on therapy response. Preclinical studies will use PDAC GEMMs and organoids combined with gain of/loss of function pharmacological and genetic manipulations to assess causal links to fibrosis, PNI and inflammation and aCDase activity. Chemotherapy and immunotherapy response will be assessed in preclinical syngeneic models. Analysis of a unique VA ERCHIVES cohort which consists of more than 800,000 annotated patients and PDAC patient biospecimen analysis will establish clinical impact. The results will lay the foundation for future therapeutic intervention of metastatic PDAC disease through the following: A. The identification of actionable biomarkers, B. The demonstrated utility of applying well-tolerated, widely used antidepressant treatments to reduce fibrosis, PNI and enhance anti-tumor immunity to improve standard of care chemotherapy and facilitate immune checkpoint inhibitor (ICB)-based therapies, and C. The validation and development of a new anti-tumor aCDase therapy. Ultimately these findings have high potential to motivate clinical approaches to reduce PDAC patient mortality.