ABSTRACT
Signaling from other angiokinases may underlie resistance to VEGF-directed therapy. We evaluated the antitumor and biologic effects of BIBF 1120 (nintedanib), a tyrosine kinase inhibitor that targets VEGF receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor in preclinical models of lung and pancreatic cancer, including models resistant to VEGF-targeted treatments. In vitro, BIBF 1120 did not show antiproliferative effects, nor did it sensitize tumor cells to chemotherapy. However, in vivo BIBF 1120 inhibited primary tumor growth in all models as a single agent and in combination with standard chemotherapy. Analysis of tumor tissue posttreatment revealed that BIBF 1120 reduced proliferation (phospho-histone 3) and elevated apoptosis (cleaved caspase-3) to a greater extent than chemotherapy alone. Furthermore, BIBF 1120 showed potent antiangiogenic effects, including decreases in microvessel density (CD31), pericyte coverage (NG2), vessel permeability, and perfusion, while increasing hypoxia. Despite the induction of hypoxia, markers of epithelial-to-mesenchymal transition (EMT) were not elevated in BIBF 1120-treated tumors. In summary, BIBF 1120 showed potent antitumor and antiangiogenic activity in preclinical models of lung and pancreatic cancer where it induced hypoxia but not EMT. The absence of EMT induction, which has been implicated in resistance to antiangiogenic therapies, is noteworthy. Together, these results warrant further clinical studies of BIBF 1120.
Subject(s)
Indoles/administration & dosage , Lung Neoplasms/drug therapy , Pancreatic Neoplasms/drug therapy , Receptors, Fibroblast Growth Factor/metabolism , Receptors, Vascular Endothelial Growth Factor/metabolism , Apoptosis/drug effects , Caspase 3/metabolism , Drug Evaluation, Preclinical , Epithelial-Mesenchymal Transition/drug effects , Humans , Hypoxia/chemically induced , Lung Neoplasms/pathology , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/genetics , Pancreatic Neoplasms/pathology , Protein Kinase Inhibitors , Receptors, Fibroblast Growth Factor/antagonists & inhibitors , Receptors, Platelet-Derived Growth Factor/antagonists & inhibitors , Receptors, Platelet-Derived Growth Factor/metabolism , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Xenograft Model Antitumor AssaysABSTRACT
INTRODUCTION: Certain chemotherapeutic agents commonly used for advanced non-small cell lung cancer (NSCLC) require minimum threshold renal function for administration. To determine how such requirements affect treatment options, we evaluated renal function patterns in this population. METHODS: We performed a single-center retrospective analysis of patients treated for stage IV NSCLC from 2000 to 2007. Associations between patient characteristics, calculated creatinine clearance (CrCl), and clinical outcomes were determined using univariate and multivariate analyses, Cox proportional hazard models, and mixed model analysis. RESULTS: 298 patients (3930 creatinine measurements) were included in the analysis. Patients had a median of 5 (interquartile range [IQR] 4-18) Cr measurements. Median baseline CrCl was 96 mL/min (IQR 74-123 mL/min); median nadir CrCl was 78 mL/min (IQR 56-100mL/min). Renal function was associated with age (P<0.001), race (P=0.009), and gender (P=0.001). 23% of patients had a recorded CrCl<60 mL/min (threshold for cisplatin), with median onset 83 days after diagnosis and median time to recover to ≥60 mL/min of 27 (IQR 3-85) days; 11% of patients had a recorded CrCl<45 mL/min (threshold for pemetrexed), with median onset 122 days after diagnosis and median recovery time of 36 (IQR 3-73) days. For both thresholds, approximately 35% of patients had no documented recovery. CONCLUSIONS: In this cohort of patients treated for stage IV NSCLC, renal function falls below commonly used thresholds for cisplatin and for pemetrexed in fewer than a quarter of patients. However, these declines may preclude administration of these drugs for prolonged periods.
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Cisplatin/administration & dosage , Creatinine/metabolism , Glutamates/administration & dosage , Glutamates/adverse effects , Guanine/analogs & derivatives , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Carcinoma, Non-Small-Cell Lung/physiopathology , Cisplatin/adverse effects , Female , Guanine/administration & dosage , Guanine/adverse effects , Humans , Kidney/drug effects , Kidney/physiology , Kidney Function Tests , Male , Middle Aged , Neoplasm Staging , Pemetrexed , Proportional Hazards Models , Retrospective Studies , Treatment OutcomeABSTRACT
GRN mutations cause frontotemporal lobar degeneration with TDP-43-positive inclusions. The mechanism of pathogenesis is haploinsufficiency. Recently, homozygous GRN mutations were detected in two patients with neuronal ceroid lipofuscinosis, a lysosomal storage disease. It is unknown whether the pathogenesis of these two conditions is related. Progranulin is cleaved into smaller peptides called granulins. Progranulin and granulins are attributed with roles in cancer, inflammation, and neuronal physiology. Cell surface receptors for progranulin, but not granulin peptides, have been reported. Revealing the cell surface receptors and the intracellular functions of granulins and progranulin is crucial for understanding their contributions to neurodegeneration.
