Inhibition of focal adhesion kinase enhances antitumor response of radiation therapy in pancreatic cancer through CD8+ T cells

Objective:Pancreatic ductal adenocarcinoma(PDAC)is a deadly malignancy,due in large part to its resistance to conventional therapies,including radiotherapy(RT).Despite RT exerting a modest antitumor response,it has also been shown to promote an immunosuppressive tumor microenvironment.Previous studies demonstrated that focal adhesion kinase inhibitors(FAKi)in clinical development inhibit the infiltration of suppressive myeloid cells and T regulatory(T regs)cells,and subsequently enhance effector T cell infiltration.FAK inhibitors in clinical development have not been investigated in combination with RT in preclinical murine models or clinical studies.Thus,we investigated the impact of FAK inhibition on RT,its potential as an RT sensitizer and immunomodulator in a murine model of PDAC.Methods:We used a syngeneic orthotopic murine model to study the effect of FAKi on hypofractionated RT.Results:In this study we showed that IN10018,a small molecular FAKi,enhanced antitumor response to RT.Antitumor activity of the combination of FAKi and RT is T cell dependent.FAKi in combination with RT enhanced CD8+T cell infiltration significantly in comparison to the radiation or FAKi treatment alone(P<0.05).FAKi in combination with radiation inhibited the infiltration of granulocytes but enhanced the infiltration of macrophages and T regs in comparison with the radiation or FAKi treatment alone(P<0.01).Conclusions:These results support the clinical development of FAKi as a radiosensitizer for PDAC and combining FAKi with RT to prime the tumor microenvironment of PDAC for immunotherapy.

Clinicopathological features and surgical outcomes of resected functional pancreatic neuroendocrine tumors: a single institution experience

Background:Functional pancreatic neuroendocrine tumors(f-PanNETs)are rare tumors of the pancreas that are associated with excess hormone production.A majority of literature available on these tumors is limited to case reports and small series and discusses a particular subtype.Here,we report the clinicopathological features and outcomes of all f-PanNETs from a high-volume pancreatectomy center.Methods:A prospectively maintained database was used to identify patients who underwent resection for f-PanNETs between January 1995 and December 2015.Patients were stratified by the type of f-PanNET,and their clinicopathological features and outcomes were analyzed and reported.Results:We identified 69 patients with a mean age of 52±16 years,and the majority were female(62%).The most common type of f-PanNET were insulinomas(70%)followed by gastrinomas(15%),and vasoactive intestinal peptidomas(VIPomas)(10%).There was considerable heterogeneity in the presenting symptoms.Patients with insulinomas presented with smaller tumors compared to the other subtypes.Nodal disease was most frequent in patients with VIPomas(71%),and gastrinomas(50%).The median overall survival(OS)was 7.4 years.Elevated Ki-67 and age>65 years were associated with poorer OS.Recurrence was observed in 8 patients(12%)and was most frequent in patients with VIPomas.Recurrence was associated with a poorer OS(P=.012).Conclusion:f-PanNETs are exceedingly rare and present with a wide variety of symptoms,histopathological findings,and outcomes.Surgical resection can help achieve good long-term survival.