Structural analysis of the interactions between a receptor and monomeric or dimeric forms of its ligand may aid in drug design.

Pancreatic ductal adenocarcinoma is an unsolved health problem with nearly 75% of patients diagnosed with advanced disease and an overall 5-year survival rate near 5%. Despite the strong link between mortality and malignancy, the mechanisms behind pancreatic cancer dissemination and metastasis are poorly understood. Correlative pathological and cell culture analyses suggest the chemokine receptor CXCR4 plays a biological role in pancreatic cancer progression. In vivo roles for the CXCR4 ligand CXCL12 in pancreatic cancer malignancy were investigated. CXCR4 and CXCR7 were consistently expressed in normal and cancerous pancreatic ductal epithelium, established cell lines, and patient-derived primary cancer cells. Relative to healthy exocrine ducts, CXCL12 expression was pathologically repressed in pancreatic cancer tissue specimens and patient-derived cell lines. To test the functional consequences of CXCL12 silencing, pancreatic cancer cell lines stably expressingthe chemokine were engineered. Consistent with a role for CXCL12 as a tumor suppressor, cells producing the chemokine wereincreasingly adherent and migration deficient in vitro and poorly metastatic in vivo, compared to control cells. Further, CXCL12 reintroduction significantly reduced tumor growth in vitro, with significantly smaller tumors in vivo, leading to a pronounced survival advantage in a preclinical model. Together, these data demonstrate a functional tumor suppressive role for the normal expression of CXCL12 in pancreatic ducts, regulating both tumor growth andcellulardissemination to metastatic sites.

Patients with pancreatic ductal adenocarcinoma (PDAC) invariably succumb to metastatic disease, but the underlying mechanisms that regulate PDAC cell movement and metastasis remain little understood. In this study, we investigated the effects of the chemokine gene CXCL12, which is silenced in PDAC tumors, yet is sufficient to suppress growth and metastasis when re-expressed. Chemokines like CXCL12 regulate cell movement in a biphasic pattern, with peak migration typically in the low nanomolar concentration range. Herein, we tested the hypothesis that the biphasic cell migration pattern induced by CXCL12 reflected a biased agonist bioenergetic signaling that might be exploited to interfere with PDAC metastasis. In human and murine PDAC cell models, we observed that nonmigratory doses of CXCL12 were sufficient to decrease oxidative phosphorylation and glycolytic capacity and to increase levels of phosphorylated forms of the master metabolic kinase AMPK. Those same doses of CXCL12 locked myosin light chain into a phosphorylated state, thereby decreasing F-actin polymerization and preventing cell migration in a manner dependent upon AMPK and the calcium-dependent kinase CAMKII. Notably, at elevated concentrations of CXCL12 that were insufficient to trigger chemotaxis of PDAC cells, AMPK blockade resulted in increased cell movement. In two preclinical mouse models of PDAC, administration of CXCL12 decreased tumor dissemination, supporting our hypothesis that chemokine-biased agonist signaling may offer a useful therapeutic strategy. Our results offer a mechanistic rationale for further investigation of CXCL12 as a potential therapy to prevent or treat PDAC metastasis. Cancer Res; 75(17); 3529–42. ©2015 AACR.

Most patients receiving chimeric antigen receptor T-cell therapy (CAR-T) for aggressive B-cell non-Hodgkin lymphoma (B-NHL) do not experience a durable remission. Several novel agents are approved to treat relapsed, refractory aggressive B-NHL; however, it remains unclear how to sequence these therapies pre– and post–CAR-T. We conducted a multicenter retrospective analysis to describe peri–CAR-T practice patterns and survival predictors for patients receiving CD19-directed CAR-T. Patients (n = 514) from 13 centers treated with CAR-T for B-NHL between 2015-2021 were included in the study. Survival curves were constructed using Kaplan-Meier method. Multivariate Cox regression analysis was used to determine the impact of the variables on survival outcomes. For all patients receiving CAR-T, a greater number of lines of therapy pre-CAR-T apheresis and bridging therapy were predictive of inferior progression-free survival (PFS) and overall survival (OS). The median PFS and OS from the time of CAR-T cell infusion were 7.6 and 25.6 months, respectively. From the time of progression post–CAR-T, the median OS was 5.5 months. The median PFS of treatments administered in the first-line post–CAR-T failure was 2.8 months. Patients with refractory disease on day 30 had inferior OS and were less likely to receive subsequent treatment(s) than other patients with CAR-T failure. Allogeneic hematopoietic cell transplantation for selected patients at any time following CAR-T failure led to durable responses in over half of patients at 1 year. These data provide a benchmark for future clinical trials in patients with post–CAR-T cell progression, which remains an unmet clinical need.