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1.
Genomics ; 113(5): 3439-3448, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34339817

RESUMO

Myxoid liposarcoma (MLPS) is a rare soft-tissue sarcoma characterised by the expression of FUS-DDIT3 chimera. Trabectedin has shown significant clinical anti-tumour activity against MLPS. To characterise the molecular mechanism of trabectedin sensitivity and of resistance against it, we integrated genomic and transcriptomic data from treated mice bearing ML017 or ML017/ET, two patient-derived MLPS xenograft models, sensitive to and resistant against trabectedin, respectively. Longitudinal RNA-Seq analysis of ML017 showed that trabectedin acts mainly as a transcriptional regulator: 15 days after the third dose trabectedin modulates the transcription of 4883 genes involved in processes that sustain adipocyte differentiation. No such differences were observed in ML017/ET. Genomic analysis showed that prolonged treatment causes losses in 4p15.2, 4p16.3 and 17q21.3 cytobands leading to acquired-resistance against the drug. The results dissect the complex mechanism of action of trabectedin and provide the basis for novel combinatorial approaches for the treatment of MLPS that could overcome drug-resistance.


Assuntos
Lipossarcoma Mixoide , Adulto , Animais , Modelos Animais de Doenças , Humanos , Lipossarcoma Mixoide/tratamento farmacológico , Lipossarcoma Mixoide/genética , Lipossarcoma Mixoide/patologia , Camundongos , Trabectedina/uso terapêutico
2.
Int J Cancer ; 147(2): 565-574, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32096871

RESUMO

High-grade serous ovarian cancer (HGS-EOCs) is generally sensitive to front-line platinum (Pt)-based chemotherapy although most patients at an advanced stage relapse with progressive resistant disease. Clinical or molecular data to identify primary resistant cases at diagnosis are not yet available. HGS-EOC biopsies from 105 Pt-sensitive (Pt-s) and 89 Pt-resistant (Pt-r) patients were retrospectively selected from two independent tumor tissue collections. Pathway analysis was done integrating miRNA and mRNA expression profiles. Signatures were further validated in silico on a cohort of 838 HGS-EOC cases from a published dataset. In all, 131 mRNAs and 5 miRNAs belonging to different functionally related molecular pathways distinguish Pt-s from Pt-r cases. Then, 17 out of 23 selected elements were validated by orthogonal approaches (SI signature). As resistance to Pt is associated with a short progression-free survival (PFS) and overall survival (OS), the prognostic role of the SI signature was assessed, and 14 genes associated with PFS and OS, in multivariate analyses (SII signature). The prognostic value of the SII signature was validated in a third extensive cohort. The expression profiles of SDF2L1, PPP1R12A and PRKG1 genes (SIII signature) served as independent prognostic biomarkers of Pt-response and survival. The study identified a prognostic molecular signature based on the combined expression profile of three genes which had never been associated with the clinical outcome of HGS-EOC. This may lead to early identification, at the time of diagnosis, of patients who would not greatly benefit from standard chemotherapy and are thus eligible for novel investigational approaches.


Assuntos
Proteína Quinase Dependente de GMP Cíclico Tipo I/genética , Cistadenocarcinoma Seroso/tratamento farmacológico , Perfilação da Expressão Gênica/métodos , Proteínas de Membrana/genética , Fosfatase de Miosina-de-Cadeia-Leve/genética , Neoplasias Ovarianas/tratamento farmacológico , Platina/uso terapêutico , Adulto , Idoso , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
4.
Int J Cancer ; 145(10): 2670-2681, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30892690

RESUMO

High-grade serous epithelial ovarian cancer (HGS-EOC) is a systemic disease, with marked intra and interpatient tumor heterogeneity. The issue of spatial and temporal heterogeneity has long been overlooked, hampering the possibility to identify those genomic alterations that persist, before and after therapy, in the genome of all tumor cells across the different anatomical districts. This knowledge is the first step to clarify those molecular determinants that characterize the tumor biology of HGS-EOC and their route toward malignancy. In our study, -omics data were generated from 79 snap frozen matched tumor biopsies, withdrawn before and after chemotherapy from 24 HGS-EOC patients, gathered together from independent cohorts. The landscape of somatic copy number alterations depicts a more homogenous and stable genomic portrait than the single nucleotide variant profile. Genomic identification of significant targets in cancer analysis identified two focal and minimal common regions (FMCRs) of amplification in the cytoband 3q26.2 (region α, 193 kb long) and 8q24.3 (region ß, 495 kb long). Analysis in two external databases confirmed regions α and ß are features of HGS-EOC. The MECOM gene is located in region α, and 15 genes are in region ß. No functional data are yet available for the genes in the ß region. In conclusion, we have identified for the first time two FMCRs of amplification in HGS-EOC, opening up a potential biological role in its etiopathogenesis.


Assuntos
Carcinoma Epitelial do Ovário/genética , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 8/genética , Variações do Número de Cópias de DNA , Neoplasias Ovarianas/genética , Biópsia , Carcinoma Epitelial do Ovário/patologia , Estudos de Coortes , Biologia Computacional , Bases de Dados Genéticas , Conjuntos de Dados como Assunto , Feminino , Genômica , Humanos , Gradação de Tumores , Neoplasias Ovarianas/patologia , Ovário/patologia , Sequenciamento do Exoma
5.
Br J Cancer ; 121(6): 464-473, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31409911

RESUMO

BACKGROUND: Myxoid 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. METHODS: Through repeated in vivo treatment in athymic nude mice, we have obtained a patient-derived xenograft with acquired resistance to trabectedin. RESULTS: At 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. CONCLUSIONS: This 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.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas de Transporte/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Lipossarcoma Mixoide/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Apoptose , Carbolinas/administração & dosagem , Proliferação de Células , Doxorrubicina/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Humanos , Lipossarcoma Mixoide/genética , Lipossarcoma Mixoide/patologia , Camundongos , Camundongos Nus , Trabectedina/administração & dosagem , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Front Genet ; 15: 1358334, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38544803

RESUMO

Thanks to a long-read sequencing (LRS) approach, in this study, we have reported a molecularly solved case of a proband with a clinical diagnosis of Cornelia de Lange syndrome (CDLS), which is a multisystemic disorder whose causative molecular defects involve cohesin complex genes, with NIPBL located at 5p13.2 accounting for approximately 50%-60% of CDLS cases. The first-tier tests revealed an abnormal karyotype 46,XY,t(5;15)(p13;q25)dn and a preserved NIPBL sequencing. Copy number variants (CNVs) at the translocation breakpoints, in disease genes, or in probably pathogenic loci were excluded by a-CGH analysis. Through fluorescence in situ hybridization (FISH) analysis on derivative chromosome 5, the breakpoint was relocated 3 Mb far from NIPBL 5'UTR, which seemed fully maintained as FISH-probe mapping to the gene showed no split signals. Moreover, tri-color FISH revealed an apparently balanced paracentric inversion including NIPBL on derivative 5. Based on the strong clinical suspicion, we evaluated the NIPBL transcript by RT-qPCR that revealed a normal amount of transcript till exon 22 and a halved amount of the transcript from exon 23 to 3'UTR, indicating the expression of a truncated transcript probably leading to a defective protein. Despite RT-qPCR confirmed the patient's CDLS clinical diagnosis, the molecular mechanism underlying this event remained to be an unsolved challenge for years. The LRS approach with nanopore technologies was able to fill the gap in this complex scenario and highlighted a chromothripsis event marked out at 5p13.2 by 36 breaks clustered in a 7.3-Mb region. The NIPBL gene was disrupted by 16 breaks and the resulting fragments were relocated in different positions and orientations. LRS confirmed the previous findings, and it has been proven to be crucial to define the complex chromosomal rearrangement in this patient which escaped current diagnostic investigations. Its application in the clinical practice will contribute to solve the unsolved.

8.
Clin Cancer Res ; 25(24): 7565-7575, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31481505

RESUMO

PURPOSE: This study was aimed at investigating whether the PPARγ agonist pioglitazone-given in combination with trabectedin-is able to reactivate adipocytic differentiation in myxoid liposarcoma (MLS) patient-derived xenografts, overcoming resistance to trabectedin. EXPERIMENTAL DESIGN: The antitumor and biological effects of trabectedin, pioglitazone, and the combination of the two drugs were investigated in nude mice bearing well-characterized MLS xenografts representative of innate or acquired resistance against trabectedin. Pioglitazone and trabectedin were given by daily oral and weekly i.v. administrations, respectively. Molecular studies were performed by using microarrays approach, real-time PCR, and Western blotting. RESULTS: We found that the resistance of MLS against trabectedin is associated with the lack of activation of adipogenesis. The PPARγ agonist pioglitazone reactivated adipogenesis, assessed by histologic and gene pathway analyses. Pioglitazone was well tolerated and did not increase the toxicity of trabectedin. The ability of pioglitazone to reactivate adipocytic differentiation was observed by morphologic examination, and it is consistent with the increased expression of genes such as ADIPOQ implicated in the adipogenesis process. The determination of adiponectin by Western blotting constitutes a good and reliable biomarker related to MLS adipocytic differentiation. CONCLUSIONS: The finding that the combination of pioglitazone and trabectedin induces terminal adipocytic differentiation of some MLSs with the complete pathologic response and cure of tumor-bearing mice provides a strong rationale to test the combination of trabectedin and pioglitazone in patients with MLS.


Assuntos
Adipócitos/patologia , Diferenciação Celular , Resistencia a Medicamentos Antineoplásicos , Lipossarcoma Mixoide/tratamento farmacológico , PPAR gama/agonistas , Pioglitazona/farmacologia , Trabectedina/farmacologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Antineoplásicos Alquilantes/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Feminino , Humanos , Hipoglicemiantes/farmacologia , Lipossarcoma Mixoide/metabolismo , Lipossarcoma Mixoide/patologia , Camundongos , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
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