UNASSIGNED: The Jak/STAT pathway is activated in @entity1 @entity1124 ( @entity1124 ) and cooperates with mutant Kras to drive initiation and progression of @entity1124 in @entity19 models. We hypothesized that the small-molecule @entity16404 inhibitor ( @entity68530 ) would elicit anti- @entity5 activity against @entity1124 and decrease immune suppressive features of the disease. We used an aggressive genetically engineered @entity1124 model with mutant KrasG12D, tp53R270H, and @entity30767 alleles (KPC- @entity30767 @entity19 ). @entity19 with confirmed @entity5 burden were treated orally with vehicle or 30 mg/kg @entity68530 daily for 14 days. Histologic analysis of pancreata from treated @entity19 revealed fewer foci of @entity420 and significantly decreased Ki67+ cells versus controls. In vivo administration of @entity68530 significantly reduced pSTAT5 and @entity3744 positive cells within the pancreas, but did not alter @entity10433 phosphorylation. Continuous dosing of KPC- @entity30767 @entity19 with @entity68530 resulted in a median survival of 108 days, as compared to a median survival of 87 days in vehicle treated animals, a 23% increase (p = 0.055). In vitro experiments demonstrated that @entity1124 cell lines were poorly sensitive to @entity68530 , requiring high micromolar concentrations to achieve targeted inhibition of Jak/STAT signaling. Similarly, @entity68530 had little in vitro effect on the viability of both @entity19 and @entity1 @entity1124 -derived stellate cell lines. However, @entity68530 potently inhibited phosphorylation of pSTAT3 and pSTAT5 at low micromolar doses in @entity1 PBMC and reduced in vitro differentiation of @entity403 + T regulatory cells. These results indicate that single agent @entity16404 i deserves further study in preclinical models of @entity1124 and has distinct inhibitory effects on @entity23117 mediated signaling.

Single agent @entity68530 @entity16404 inhibitor has distinct inhibitory effects on @entity23117 signaling in genetically engineered XXXX with pancreatic cancer.

@entity1 :: ('9606', 'Species') :: ['human'] @entity16404 :: ('16452(Tax:10090)', 'Gene') :: ['Jak2'] @entity3744 :: ('20371(Tax:10090)', 'Gene') :: ['FoxP3'] @entity1124 :: ('MESH:D021441', 'Disease') :: ['PDAC', 'pancreatic ductal adenocarcinoma'] @entity30767 :: ('12189(Tax:10090)', 'Gene') :: ['Brca1'] @entity19 :: ('10090', 'Species') :: ['mice', 'Mice', 'murine'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumor'] @entity10433 :: ('20848(Tax:10090)', 'Gene') :: ['STAT3'] @entity403 :: ('50943', 'Gene') :: ['Foxp3'] @entity68530 :: ('MESH:C571029', 'Chemical') :: ['BMS-911543'] @entity23117 :: ('20850(Tax:10090)', 'Gene') :: ['STAT5'] @entity420 :: ('MESH:D000230', 'Disease') :: ['adenocarcinoma']
@entity19 :: (10090,Species) :: ['mice']
