ABSTRACT
BACKGROUND: This study evaluated the efficacy and safety of ziv-aflibercept in combination with cisplatin and pemetrexed in non-small cell lung cancer (NSCLC). METHODS: This single arm, multicentre phase II trial enrolled patients with previously untreated, locally advanced or metastatic non-squamous NSCLC. Patients received intravenous ziv-aflibercept 6 mg kg(-1), pemetrexed 500 mg m(-2), and cisplatin 75 mg m(-2), every 21 days for up to six cycles. Maintenance administration of ziv-aflibercept was to continue until disease progression, intolerable toxicity or other cause for withdrawal. The co-primary end points were objective response rate (ORR) and progression-free survival (PFS). Planned sample size was 72 patients. RESULTS: The study was closed prematurely because of three confirmed and two suspected cases of reversible posterior leukoencephalopathy syndrome (RPLS). A total of 42 patients were enrolled. Median age was 61.5 years; 55% were male, 86% Caucasian and 50% had Eastern Cooperative Oncology Group performance status (ECOG PS)=0. A median of four cycles of ziv-aflibercept was administered. The most common treatment-emergent adverse events (TEAEs) of any grade were nausea (69%) and fatigue (67%), with hypertension (36%) as the most common grade 3/4 TEAE. Of the 38 evaluable patients, ORR was 26% and median PFS was 5 months. CONCLUSION: Cases of RPLS had been observed in other studies in the ziv-aflibercept clinical development programme but the rate observed in this study was higher than previously observed. This might be related to declining renal function and/or hypertension. Although ORR and PFS were in accordance with most historical first-line NSCLC studies, this combination of ziv-aflibercept/cisplatin/pemetrexed will not be further explored in NSCLC.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carcinoma, Non-Small-Cell Lung/drug therapy , Cisplatin/administration & dosage , Glutamates/administration & dosage , Guanine/analogs & derivatives , Receptors, Vascular Endothelial Growth Factor/administration & dosage , Recombinant Fusion Proteins/administration & dosage , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Cisplatin/adverse effects , Disease-Free Survival , Drug-Related Side Effects and Adverse Reactions/classification , Drug-Related Side Effects and Adverse Reactions/pathology , Female , Glutamates/adverse effects , Guanine/administration & dosage , Guanine/adverse effects , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Pemetrexed , Receptors, Vascular Endothelial Growth Factor/adverse effects , Recombinant Fusion Proteins/adverse effects , Treatment OutcomeABSTRACT
Myristylation of FBR v-fos, a c-fos retroviral homologue that causes osteosarcomas in mice, determines many of its transcriptional properties in vitro. To determine whether myristylation of FBR v-fos contributes to in vivo tumorigenicity, we examined its transforming capability in comparison to a nonmyristylated FBR v-fos (G2A-R). Retroviral infections with FBR v-fos and G2A-R transform BALB/c-3T3 cells. The number, size, and cellular morphology of foci generated by both FBR and G2A-R are indistinguishable. However, marked biological differences were found in transgenic mice expressing either the myristylated FBR v-fos or the nonmyristylated G2A-R. 11 of 26 FBR v-fos transgenic mice died as a result of gross tumor burden. None of the 28 G2A-R transgenic mice died from tumor burden, and only two of the G2A-R mice developed bone tumors. Histologic examination of the tumors reveals that the FBR v-fos bone tumors contain malignant cells with features of four cell lineages (osteocytes, chondrocytes, myocytes, and adipocytes) in an environment rich in extracellular matrix (ECM). However, the G2A-R tumors exist in an environment devoid of ECM and display malignant cells with features of adipocytes. Masson staining reveals that the ECM of the FBR tumors stains strongly for collagen. Immunohistochemical staining with collagen III antibody demonstrates an abundance of collagen III expression in this ECM. While NH2-terminal myristylation is not required for FBR immortalization and transformation, it is essential in determining the degree of differentiation and tumorigenicity of malignant cells.
Subject(s)
Cell Transformation, Neoplastic , Myristic Acids/metabolism , Oncogene Proteins v-fos/metabolism , Osteosarcoma/pathology , Protein Processing, Post-Translational , Sarcoma Viruses, Murine/genetics , 3T3 Cells , Animals , Base Sequence , Cell Differentiation , Mice , Mice, Inbred BALB C , Mice, Transgenic , Moloney murine leukemia virus/genetics , Myristic Acid , Osteosarcoma/genetics , Polymerase Chain Reaction , Repetitive Sequences, Nucleic AcidABSTRACT
Viral oncogenes are generally believed to cause transformation through disregulated mimicry of their cellular homologues. However, here we show that FBR v-fos, unlike c-fos, transcriptionally activates unique genes in retrovirally induced chondro-osseous sarcomas. We show that FBR v-fos transactivates the collagen III and stromelysin promoters and that the unique transcriptional properties of transforming FBR depend upon its N-terminal myristylation and the differentiation state of the cell. Deletion or mutation of the myristylation site results in a loss of FBR v-fos transactivation in HeLa and undifferentiated 3T3-L1 preadipocyte cell lines. FBR v-fos transactivation of collagen III maps to a negative regulatory site which binds a key regulator of adipocyte differentiation, C/EBP alpha. Cotransfection of C/EBP alpha abolishes FBR v-fos transactivation of the alpha 1(III) collagen promoter. Furthermore, FBR v-fos cannot transactivate collagen III subsequent to adipocyte differentiation. We also demonstrate that collagen III transcription is reduced during adipocyte differentiation as the transcriptional activity of C/EBP alpha is concomitantly induced. Our results indicate that FBR v-fos transactivation depends upon its cotranslational myristylation and maps to a negative regulatory region which binds C/EBP alpha.
Subject(s)
DNA-Binding Proteins/metabolism , Gene Expression Regulation , Nuclear Proteins/metabolism , Oncogene Proteins v-fos/metabolism , Protein Processing, Post-Translational , Transcriptional Activation , Adipocytes/physiology , Animals , Base Sequence , CCAAT-Enhancer-Binding Proteins , Cell Differentiation/genetics , Cell Transformation, Neoplastic , Cell Transformation, Viral , Collagen/genetics , DNA Mutational Analysis , DNA-Binding Proteins/genetics , HeLa Cells/metabolism , Humans , Matrix Metalloproteinase 3 , Metalloendopeptidases/genetics , Models, Genetic , Molecular Sequence Data , Myristates/metabolism , Nuclear Proteins/genetics , Oncogene Proteins v-fos/genetics , Oncogene Proteins v-fos/isolation & purification , Promoter Regions, Genetic/genetics , Protein Binding , Sarcoma/metabolism , Transcription, GeneticABSTRACT
FBR murine sarcoma virus (gag-fos) protein, a virally transduced Fos protein, exhibits decreased gene transactivation in comparison with the cellular Fos protein. Biochemical analysis suggests that myristylation of the virally encoded N-terminal gag region results in decreased DNA binding and transcriptional activation without affecting heterodimerization with Jun protein. These findings demonstrate that protein myristylation can modulate gene regulation by a DNA-binding protein.
