oxadiazoles and Sarcoma--Ewing

Tumor vasculature is innately dysfunctional. Poorly functional tumor vessels inefficiently deliver chemotherapy to tumor cells; vessel hyper-permeability promotes chemotherapy delivery primarily to a tumor's periphery. Here, we identify a method for enhancing chemotherapy efficacy in Ewing sarcoma (ES) in mice by modulating tumor vessel permeability. Vessel permeability is partially controlled by the G protein-coupled Sphinosine-1-phosphate receptors 1 and 2 (S1PR1 and S1PR2) on endothelial cells. S1PR1 promotes endothelial cell junction integrity while S1PR2 destabilizes it. We hypothesize that an imbalance of S1PR1:S1PR2 is partially responsible for the dysfunctional vascular phenotype characteristic of ES and that by altering the balance in favor of S1PR1, ES vessel hyper-permeability can be reversed. In our study, we demonstrate that pharmacologic activation of S1PR1 by SEW2871 or inhibition of S1PR2 by JTE-013 caused more organized, mature and functional tumor vessels. Importantly, S1PR1 activation or S1PR2 inhibition improved antitumor efficacy. Our data suggests that pharmacologic targeting of S1PR1 and S1PR2 may be a useful adjuvant to standard chemotherapy for ES patients.

Topics: Animals; Antibiotics, Antineoplastic; Bone Neoplasms; Capillary Permeability; Cell Line, Tumor; Doxorubicin; Endothelial Cells; Humans; Mice, Nude; Oxadiazoles; Pyrazoles; Pyridines; Sarcoma, Ewing; Sphingosine 1 Phosphate Receptor Modulators; Sphingosine-1-Phosphate Receptors; Thiophenes; Treatment Outcome; Xenograft Model Antitumor Assays

There is an imperious need for the development of novel therapeutics for the treatment of Ewing sarcoma, the second most prevalent solid bone tumour observed in children and young adolescents. Recently, a 4-nitrobenzofuroxan derivative, XI-006 (NSC207895) was shown to diminish MDM4 promoter activity in breast cancer cell lines. As amplification of MDM4 is frequently observed in sarcomas, this study examined the therapeutic potential of XI-006 for the treatment of Ewing and osteosarcoma. XI-006 treatment of Ewing and osteosarcoma cell lines (n = 11) resulted in rapid and potent apoptosis at low micro-molar concentrations specifically in Ewing sarcoma cell lines (48 hr IC50 0.099-1.61 μM). Unexpectedly, apoptotic response was not dependent on MDM4 mRNA/protein levels or TP53 status. Alkaline/neutral comet and γH2AX immunofluorescence assays revealed that the cytotoxic effects of XI-006 could not be attributed to the induction of DNA damage. RNA expression analysis revealed that the mechanism of action of XI-006 could be accredited to the inhibition of cell division and cycle regulators such as KIF20A and GPSM2. Finally, potent synergy between XI-006 and olaparib (PARP inhibitor) were observed due to the down-regulation of Mre11. Our findings suggest that XI-006 represents a novel therapeutic intervention for the treatment of Ewing sarcoma.

Topics: Antineoplastic Agents; Apoptosis; Bone Neoplasms; Calcium-Binding Proteins; Carrier Proteins; Cell Adhesion Molecules; Cell Cycle Proteins; Cell Division; Cell Line, Tumor; Cyclic N-Oxides; DNA Damage; DNA-Binding Proteins; Histones; Humans; Intracellular Signaling Peptides and Proteins; Kinesins; Membrane Proteins; MRE11 Homologue Protein; Nuclear Proteins; Oxadiazoles; Phthalazines; Piperazines; Promoter Regions, Genetic; Proto-Oncogene Proteins; Sarcoma, Ewing; Tumor Suppressor Protein p53; Utrophin

The improvement of Ewing sarcoma (EWS) therapy is currently linked to the discovery of strategies to select patients with poor and good prognosis and of modified treatment regimens. In this study, we analyzed the molecular factors governing EWS response to chemotherapy to identify genetic signatures to be used for risk-adapted therapy.. Microarray technology was used for profiling 30 primary tumors and seven metastases of patients who were classified according to event-free survival. For selected genes, real-time polymerase chain reaction was applied in 42 EWS primary tumors as validation assay. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test was used to evaluate in vitro drug sensitivity.. We identified molecular signatures that reflect tumor resistance to chemotherapy. Annotation analysis was applied to reveal the biologic functions that critically influenced clinical outcome. The prognostic relevance of glutathione metabolism pathway was validated. The expression of MGST1, the microsomal glutathione S-transferase (GST), was found to clearly predict EWS prognosis. MGST1 expression was associated with doxorubicin chemosensitivity. This prompted us to assess the in vitro effectiveness of 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX), a new anticancer agent that efficiently inhibits GST enzymes. Six cell lines were found to be sensitive to this new drug.. Classification of EWS patients into high- and low-risk groups is feasible with restricted molecular signatures that may have practical value at diagnosis for selecting patients with EWS who are unresponsive to current treatments. Glutathione metabolism pathway emerged as one of the most significantly altered prognosis-associated pathway. NBDHEX is proposed as a new potential therapeutic possibility.

Topics: Antineoplastic Agents; Bone Neoplasms; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Gene Expression Profiling; Glutathione S-Transferase pi; Glutathione Transferase; Humans; Male; Oxadiazoles; Principal Component Analysis; Prognosis; Sarcoma, Ewing

Topics: Adolescent; Anti-Inflammatory Agents; Bronchitis; Child; Child, Preschool; Citrates; Female; Gastrointestinal Diseases; Growth; Humans; Infant; Infant, Newborn; Leukemia; Lung Neoplasms; Muscles; Osteosarcoma; Oxadiazoles; Pyloric Stenosis; Sarcoma; Sarcoma, Ewing