ABSTRACT
PURPOSE: Dedifferentiated liposarcoma (DDLS), one of the most common and aggressive sarcomas, infrequently responds to chemotherapy. DDLS survival and growth depend on underexpression of C/EBPα, a tumor suppressor and transcriptional regulator controlling adipogenesis. We sought to screen and prioritize candidate drugs that increase C/EBPα expression and may therefore serve as differentiation-based therapies for DDLS. EXPERIMENTAL DESIGN: We screened known bioactive compounds for the ability to restore C/EBPα expression and inhibit proliferation selectively in two DDLS cell lines but not in normal adipose-derived stem cells (ASC). Selected hits' activity was validated, and the mechanism of the most potent, SN-38, was investigated. The in vivo efficacy of irinotecan, the prodrug of SN-38, was evaluated in DDLS xenograft models. RESULTS: Of 3,119 compounds, screen criteria were met by 19. Validation experiments confirmed the DDLS selectivity of deguelin, emetine, and SN-38 and showed that they induce apoptosis in DDLS cells. SN-38 had the lowest IC50 (approximately 10 nmol/L), and its pro-apoptotic effects were countered by knockdown of CEBPA but not of TP53. Irinotecan significantly inhibited tumor growth at well-tolerated doses, induced nuclear expression of C/EBPα, and inhibited HIF1α expression in DDLS patient-derived and cancer cell line xenograft models. In contrast, doxorubicin, the most common treatment for nonresectable DDLS, reduced tumor growth by 30% to 50% at a dose that caused weight loss. CONCLUSIONS: This high-content screen revealed potential treatments for DDLS. These include irinotecan, which induces apoptosis of DDLS cells in a C/EBPα-dependent, p53-independent manner, and should be clinically evaluated in patients with advanced DDLS.
Subject(s)
CCAAT-Enhancer-Binding Protein-alpha , CCAAT-Enhancer-Binding Proteins , Liposarcoma , Adipocytes/metabolism , CCAAT-Enhancer-Binding Protein-alpha/analysis , CCAAT-Enhancer-Binding Protein-alpha/metabolism , CCAAT-Enhancer-Binding Proteins/analysis , Genes, Tumor Suppressor , Humans , Liposarcoma/drug therapy , Liposarcoma/genetics , Liposarcoma/pathology , Stem Cells/metabolismABSTRACT
Myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS) are highly genetically complex soft tissue sarcomas. Up to 50% of patients develop distant metastases, but current systemic therapies have limited efficacy. MFS and UPS have recently been shown to commonly harbor copy number alterations or mutations in the tumor suppressor genes RB1 and TP53. As these alterations have been shown to engender dependence on the oncogenic protein Skp2 for survival of transformed cells in mouse models, we sought to examine its function and potential as a therapeutic target in MFS/UPS. Comparative genomic hybridization and next-generation sequencing confirmed that a significant fraction of MFS and UPS patient samples (n = 94) harbor chromosomal deletions and/or loss-of-function mutations in RB1 and TP53 (88% carry alterations in at least one gene; 60% carry alterations in both). Tissue microarray analysis identified a correlation between absent Rb and p53 expression and positive expression of Skp2. Downregulation of Skp2 or treatment with the Skp2-specific inhibitor C1 revealed that Skp2 drives proliferation of patient-derived MFS/UPS cell lines deficient in both Rb and p53 by degrading p21 and p27. Inhibition of Skp2 using the neddylation-activating enzyme inhibitor pevonedistat decreased growth of Rb/p53-negative patient-derived cell lines and mouse xenografts. These results demonstrate that loss of both Rb and p53 renders MFS and UPS dependent on Skp2, which can be therapeutically exploited and could provide the basis for promising novel systemic therapies for MFS and UPS. SIGNIFICANCE: Loss of both Rb and p53 renders myxofibrosarcoma and undifferentiated pleomorphic sarcoma dependent on Skp2, which could provide the basis for promising novel systemic therapies.See related commentary by Lambert and Jones, p. 2437.
Subject(s)
Fibrosarcoma , Sarcoma , Soft Tissue Neoplasms , Adult , Animals , Comparative Genomic Hybridization , Fibrosarcoma/genetics , Humans , Mice , Sarcoma/genetics , Tumor Suppressor Protein p53/geneticsABSTRACT
Este estudio esta referido a la subestacion Caiconi cubre la coordinacion de la proteccion del equipo de tableros (Electric Switchgear)6.9 kV y el transformador de potencia de 7.5/9.9 MVA, tomando en cuenta los principios basicos de un optimo sistema de proteccion, a saber: confiabilidad-un sistema robusto y listo para actuar en cualquier circunstancia; selectividad-maxima continuidad del servicio, aislando solamente la parte del sistema con problemas; velocidad-limitar al minimo posible, el tiempo de duracion de las fallas, reduciendo asi la posibilidad de daños a los equipos; simplicidad-menor equipamiento y cableado.
