Correction: Establishment and characterisation of a new patient-derived model of myxoid liposarcoma with acquired resistance to trabectedin.
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ABSTRACT:
SUBMITTER: Bello E
PROVIDER: S-EPMC7109093 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundMyxoid liposarcoma is a histological subtype of liposarcoma particularly sensitive to trabectedin. In clinical use this drug does not cause cumulative toxicity, allowing prolonged treatment, generally until disease progression. No other effective therapies are available for trabectedin-resistant patients.MethodsThrough repeated in vivo treatment in athymic nude mice, we have obtained a patient-derived xenograft with acquired resistance to trabectedin.ResultsAt basal level, the morphology of the resistant and sensitive models did not differ, in keeping with the finding that the transcriptional profiles of the resistant and sensitive tumours were very similar. After trabectedin treatment adipogenesis was induced in the parental xenograft but not in the resistant one, as assessed by pathological and molecular analysis. A defective transcription-coupled-nucleotide excision repair in the resistant tumour due to mutation of the UVSSA gene may be implicated in the mechanism of resistance.ConclusionsThis is the first in vivo model of myxoid liposarcoma with acquired resistance to trabectedin. Although further studies are necessary to characterise the resistance mechanisms, this is a useful tool for studying new therapeutic strategies to overcome trabectedin resistance in patients.
| S-EPMC6738121 | biostudies-literature
Project description: Not available
| S-EPMC6510721 | biostudies-literature
Project description:Myxoid liposarcoma (MLS) is the second most common type of liposarcoma, and today few model systems to study the disease exists. To be able to model the disease in vitro, cell-free scaffolds from MLS patient-derived xenograft (PDX) models were generated. The MLS scaffolds were then used as a 3D growth platform for MLS cell lines to study the cancer microenvironments impact on cellular heterogeneity using RNA sequencing. Key components in the microenvironment have also been shown to influence the fraction of cellular subpopulations, such as cancer stem cells and migratory cells but also to promote aggressive features of cancers. Therefore, to better understand and characterize these scaffolds, protein analyses were performed and links between scaffold compositions and the induced gene expression profiles of the cells grown therein could be made. This model system provides a better insight to the composition of the cell-free cancer microenvironment in a rare disease, which can lead to identification of novel malignancy inducing properties in MLS.
2024-05-08 | PXD023792 | Pride
Project description:INTRODUCTION:Myxoid/round-cell liposarcoma (MRCL) is a specific histological subtype that accounts for 30-35% of liposarcomas and whose virulence depends on the quantity of round-cells within the tumor. MRCL is associated with specific chromosomal translocations resulting in the formation of CHOP/FUS and CHOP/EWS fusion proteins. A high sensitivity of MRCL to trabectedin was reported. CASE REPORT:We report the case of a 63-year-old woman with a bulky and metastatic MRCL, treated with trabectedin 1.5 mg/m(2) as a first-line treatment. She experienced a long-lasting clinical benefit. The patients received 14 cycles of trabectedin and achieved a durable partial response to the metastases and a stable disease of the primary tumor, which is a very favorable safety profile. Also noteworthy is that we have observed a calcification of the primary tumor and the metastasis. The response, which lasted 30 months, led to a symptomatic improvement, associated with an excellent general condition and an absence of pain. CONCLUSION:To the best of our knowledge, this is the first report of a MRCL treated with trabectedin that resulted in a calcification of the primary tumor and the metastases, associated with an outstandingly long response. This case suggests that trabectedin may represent a feasible first-line therapeutic option for patients with MRCL, with meaningful clinical benefits and an acceptable safety profile.
| S-EPMC3999575 | biostudies-literature
Project description:Transcriptional profiling of patient-derived xenograft models of myxoid liposarcoma with either FUS-CHOP type I, named as ML017, or FUS-CHOP type III, named as ML006. Both ML017 and ML006 are responsive to trabectedin treatment, while model ML017/ET has aquired resistance to the drug. Samples are either under untreated conditions, or treated either with trabectedin or pioglitazone or both.
2020-01-10 | E-MTAB-8632 | biostudies-arrayexpress
Project description:Trabectedin, a new antitumor compound originally derived from a marine tunicate, is clinically effective in soft tissue sarcoma. The drug has shown a high selectivity for myxoid liposarcoma, characterized by the translocation t(12;16)(q13; p11) leading to the expression of FUS-CHOP fusion gene. Trabectedin appears to act interfering with mechanisms of transcription regulation. In particular, the transactivating activity of FUS-CHOP was found to be impaired by trabectedin treatment. Even after prolonged response resistance occurs and thus it is important to elucidate the mechanisms of resistance to trabectedin. To this end we developed and characterized a myxoid liposarcoma cell line resistant to trabectedin (402-91/ET), obtained by exposing the parental 402-91 cell line to stepwise increases in drug concentration. The aim of this study was to compare mRNAs, miRNAs and proteins profiles of 402-91 and 402-91/ET cells through a systems biology approach. We identified 3,083 genes, 47 miRNAs and 336 proteins differentially expressed between 402-91 and 402-91/ET cell lines. Interestingly three miRNAs among those differentially expressed, miR-130a, miR-21 and miR-7, harbored CHOP binding sites in their promoter region. We used computational approaches to integrate the three regulatory layers and to generate a molecular map describing the altered circuits in sensitive and resistant cell lines. By combining transcriptomic and proteomic data, we reconstructed two different networks, i.e. apoptosis and cell cycle regulation, that could play a key role in modulating trabectedin resistance. This approach highlights the central role of genes such as CCDN1, RB1, E2F4, TNF, CDKN1C and ABL1 in both pre- and post-transcriptional regulatory network. The validation of these results in in vivo models might be clinically relevant to stratify myxoid liposarcoma patients with different sensitivity to trabectedin treatment.
| S-EPMC3327679 | biostudies-literature
Project description:ImportancePreclinical data about the synergistic activity of radiotherapy (RT) and trabectedin have been reported. The combination of trabectedin and RT in treating myxoid liposarcomas appears worth exploring.ObjectiveTo explore the effectiveness and safety of trabectedin combined with RT.Design, setting, and participantsThis international, open-label, phase 2 nonrandomized clinical trial including 46 patients with myxoid liposarcoma was conducted in 4 centers in Spain, 1 in Italy, and 2 in France from July 1, 2016, to September 30, 2019. Eligible patients had to have a histologic, centrally reviewed diagnosis of localized resectable myxoid liposarcoma arising from an extremity or the trunk wall.InterventionsTrabectedin was administered at the recommended dose stemming from the phase 1 trial (1.5 mg/m2), with intravenous infusion during 24 hours every 21 days for a total of 3 cycles. Radiotherapy was started after completion of the first trabectedin infusion (cycle 1, day 2). Patients received 25 fractions of radiation for a total of 45 Gy. Surgery was planned 3 to 4 weeks after the administration of the last preoperative cycle and not until 4 weeks after the end of preoperative RT. Pathologic specimens were mapped in tumor sections to estimate the histologic changes and the percentage of viable tumor after neoadjuvant treatment.Main outcomes and measuresThe primary objective of the phase 2 part of the study was overall response. Secondary objectives were effectiveness measured by relapse-free survival and activity measured by functional imaging and pathologic response.ResultsA total of 46 patients were enrolled. Four patients were not evaluable. The median age was 43 years (range, 18-77 years), and 31 patients were male (67%). Overall, 9 of 41 patients (22%) achieved a partial response with neoadjuvant treatment with trabectedin and RT, with 5 of 39 patients (13%) achieving a complete pathologic response and 20 of 39 patients (51%) having 10% or less of a viable remaining tumor. Partial responses according to Choi criteria were observed in 24 of 29 evaluable patients (83%), and no patient had disease progression. Treatment was well tolerated.Conclusions and relevanceAlthough the primary end point of this phase 2 nonrandomized clinical trial was not met (Response Evaluation Criteria in Solid Tumors response in ≥70% of patients), results suggest this combination was well tolerated and effective in terms of pathologic response. Thus, trabectedin plus RT might be a treatment option regarding tolerability; further evidence should be generated in this setting.
| S-EPMC10064283 | biostudies-literature
Project description:To elucidate the mechanisms behind the high sensitivity of myxoid/round cell liposarcoma (MRCL) to trabectedin and the suggested selectivity for specific subtypes we have developed and characterized two MRCL xenografts differing for the breakpoint of the fusion gene FUS- HOP, respectively of type II and III. Transcription profiling experiments were carried out after trabectidin treatment in four separate time points (control, 24h after the first dose, 24h after the third dose, and 15 days after the third dose) for both types of xenografts in order to identify genes and pathways involved with the mechanisms of action of trabectedin in MRCL.
2013-12-10 | E-MTAB-1809 | biostudies-arrayexpress
Project description:Glioblastoma is an aggressive brain tumour with a patient median survival of approximately 14 months. The development of innovative treatment strategies to increase the life span and quality of life of patients is hence essential. This requires the use of appropriate glioblastoma models for preclinical testing, which faithfully reflect human cancers. The aim of this study was to establish glioblastoma patient-derived xenografts (PDXs) by heterotopic transplantation of tumour pieces in the axillae of NMRI nude mice. Ten out of 22 patients' samples gave rise to tumours in mice. Their human origin was confirmed by microsatellite analyses, though minor changes were observed. The glioblastoma nature of the PDXs was corroborated by pathological evaluation. Latency times spanned from 48.5 to 370.5 days in the first generation. Growth curve analyses revealed an increase in the growth rate with increasing passages. The methylation status of the MGMT promoter in the primary material was maintained in the PDXs. However, a trend towards a more methylated pattern could be found. A correlation was observed between the take in mice and the proportion of Sox2+ cells (r = 0.49, p = 0.016) and nestin+ cells (r = 0.55, p = 0.007). Our results show that many PDXs maintain key features of the patients' samples they derive from. They could thus be used as preclinical models to test new therapies and biomarkers.
| S-EPMC7226316 | biostudies-literature
Project description:BackgroundMyxoid liposarcoma (MLS) has the tendency to metastasize extrapulmonary. Although prognostic factors at the initial diagnosis of MLS have been reported, those at diagnosis of metastasis remain unclear. The purpose of this study was to investigate the prognostic factors for disease-specific survival at the initial diagnosis of metastasis.MethodsThis retrospective observational study was conducted at three cancer centers and two university hospitals in Japan. Of 274 MLS patients pathologically diagnosed between 2001 and 2015, 48 metastatic patients were examined.ResultsLung metastases were detected in nine patients (18.8%) and extrapulmonary metastases in 45 (93.8%). Interval from primary diagnosis to the first metastasis was significantly shorter in patients with lung metastases than without (p = 0.007). Median disease-specific survival after diagnosis of metastases was 52.5 months in all patients. In multivariable analysis, liver metastasis (hazard ratio (HR), 2.71 [95% confidence interval (CI), 1.00-7.09]) and no evidence of disease (NED) achieved by radical treatment (resection with or without radiation therapy, or radiation therapy ≥60 Gy) or semi-radical (radiation therapy ≥40 Gy) treatment were significantly related to survival (HR, 0.36; 95%CI [0.13-0.95]). The number of metastases (odds ratio (OR), 0.44; 95%CI [0.25-0.78]) and abdominal/retroperitoneal metastases (OR, 0.09; 95%CI [0.008-0.95]) were the significant inhibitory factors of achieving NED.ConclusionsThis is the first study to statistically demonstrate the importance of achieving NED with surgical resection or radiation therapy for longer survival in metastatic MLS patients. As number of metastases was a significant factor for achieving NED, early detection of metastases might be important.
| S-EPMC7491192 | biostudies-literature