Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

BACKGROUND & AIMS: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress, and novel therapeutic response in PC to develop a biomarkerdriven therapeutic strategy targeting DDR and replication stress in PC. METHODS: We interrogated the transcriptome, genome, proteome, and functional characteristics of 61 novel PC patient–derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient-derived xenografts and human PC organoids. RESULTS: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors, including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, cosegregates with response to platinum (P < .001) and PARP inhibitor therapy (P < .001) in vitro and in vivo. We generated a novel signature of replication stress that predicts response to ATR (P < .018) and WEE1 inhibitor (P < .029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < .001) but was not associated with DDR deficiency. CONCLUSIONS: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR-proficient PC and after platinum therapy.Stephan B. Dreyer ... Karin S. Kassahn ... et al

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P &lt; 0.001) and PARP inhibitor therapy (P &lt; 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P &lt; 0.018) and WEE1 inhibitor (P &lt; 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P &lt; 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Profiles of centenarians' functioning: linking functional and cognitive capacity with depressive symptoms.

Despite most centenarians facing age-related declines in functional and cognitive capacities, the severity of these declines varies among individuals, as does the maintenance of good mental health (e.g., depressive symptoms) despite these declines. This study aims to examine this heterogeneity in centenarians from the Second Heidelberg Centenarian Study, which collected data from 112 centenarians living in Germany. In our study, we focus on a subsample of 73 centenarians who provided self-reports for our measures of interest (M age = 100.4, SD age = 0.55). We examined correlations between functional capacity (i.e., PADL, IADL), cognitive capacity (i.e., MMSE), and depressive symptoms (i.e., GDS), and the existence of different profiles using hierarchical clustering. Higher functional capacity was related to higher cognitive capacity and to fewer depressive symptoms. Yet, higher cognitive capacity was associated with more depressive symptoms. Hierarchical clustering analysis elucidated this contradiction by identifying three profiles: low-capacity individuals (i.e., 24 individuals had low functional and cognitive capacities, with low depressive symptoms), high-capacity individuals (i.e., 33 individuals with high functional and cognitive capacities, with low depressive symptoms), and low-functional-high-cognitive-capacity individuals (i.e., 16 individuals showed low functional but high cognitive capacity, with high depressive symptoms). Our post-hoc analyses highlighted arthritis and pain as risk factors for functional dependence and depression. Our findings emphasize the importance of identifying centenarian subgroups with specific resource- and risk profiles to better address their needs, and of treating pain to improve functional capacity and mental health in centenarians