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1.
Sci Rep ; 11(1): 3176, 2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33542435

RESUMO

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, lacking effective therapy. Many TNBCs show remarkable response to carboplatin-based chemotherapy, but often develop resistance over time. With increasing use of carboplatin in the clinic, there is a pressing need to identify vulnerabilities of carboplatin-resistant tumors. In this study, we generated carboplatin-resistant TNBC MDA-MB-468 cell line and patient derived TNBC xenograft models. Mass spectrometry-based proteome profiling demonstrated that carboplatin resistance in TNBC is linked to drastic metabolism rewiring and upregulation of anti-oxidative response that supports cell replication by maintaining low levels of DNA damage in the presence of carboplatin. Carboplatin-resistant cells also exhibited dysregulation of the mitotic checkpoint. A kinome shRNA screen revealed that carboplatin-resistant cells are vulnerable to the depletion of the mitotic checkpoint regulators, whereas the checkpoint kinases CHEK1 and WEE1 are indispensable for the survival of carboplatin-resistant cells in the presence of carboplatin. We confirmed that pharmacological inhibition of CHEK1 by prexasertib in the presence of carboplatin is well tolerated by mice and suppresses the growth of carboplatin-resistant TNBC xenografts. Thus, abrogation of the mitotic checkpoint by CHEK1 inhibition re-sensitizes carboplatin-resistant TNBCs to carboplatin and represents a potential strategy for the treatment of carboplatin-resistant TNBCs.

2.
Int J Cancer ; 148(2): 307-319, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32851660

RESUMO

Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two-sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels (P < 5 × 10-8 ) were identified as instrumental variables, and assessed using genome-wide association study data from the Endometrial Cancer Association Consortium (12 906 cases and 108 979 controls) and the Global Lipids Genetic Consortium (n = 188 578). Mendelian randomization analyses found genetically raised LDL cholesterol levels to be associated with lower risks of endometrial cancer of all histologies combined, and of endometrioid and non-endometrioid subtypes. Conversely, higher genetically predicted HDL cholesterol levels were associated with increased risk of non-endometrioid endometrial cancer. After accounting for the potential confounding role of obesity (as measured by genetic variants associated with body mass index), the association between genetically predicted increased LDL cholesterol levels and lower endometrial cancer risk remained significant, especially for non-endometrioid endometrial cancer. There was no evidence to support a role for triglycerides in endometrial cancer development. Our study supports a role for LDL and HDL cholesterol in the development of non-endometrioid endometrial cancer. Further studies are required to understand the mechanisms underlying these findings.

3.
Front Oncol ; 10: 538064, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33194598

RESUMO

In cancer, upregulation of coinhibitory B7 ligands has been associated with immune evasion. So far, anti-programmed death-1 (PD-1) and anti-PD-ligand 1 (PD-L1) antibodies have been used in immuno-oncology, with promising outcomes; however, it is still needed to identify other markers, especially for endometrial cancer (EC). EC is a gynecological malignancy historically classified into two types: type I, with mostly estrogen-dependent endometrioid diseases, and the most aggressive type II, including mainly estrogen-independent and non-endometrioid tumors. PD ligand-2 (PD-L2) is known as the second ligand of the PD-1 receptor and, upon its binding, contributes to T-cell exhaustion. Up to now, very few information are available about PD-L2 in cancers, and no data have been reported for EC. The aim of this work was to characterize the PD-L1 and PD-L2 ligand expression profile in EC cell lines, focusing the attention on the biological role of PD-L2 and its prognostic impact in human type II EC biopsies. Using in silico analysis of TCGA data, we performed a molecular profiling in a cohort of 506 patients, both types I and II, and PD-1 ligands expression was also analyzed in different primary human EC cell lines. Moreover, PD-L2 staining was evaluated in a cohort of human type II EC samples and correlated with the overall survival (OS), progression-free survival (PFS), and additional clinicopathological data. From the in silico analysis, PD-L2 was more expressed than PD-L1 in EC cell lines. PD-L2 was found highly expressed in 64.44% of tumor specimens, predominantly in the serous subtype, in both stromal and epithelial components, while in peritumoral and normal tissues it was predominantly moderate or low. In vitro, we investigated the cell autonomous role of PD-L2 in controlling cell survival, migration, and chemoresistance.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33144283

RESUMO

BACKGROUND: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers. METHODS: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e. inverse-variance meta-analysis, co-localization, and M-values), and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data. RESULTS: Genetic correlation analysis revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10-5). We found seven loci associated with risk for both cancers (PBonferroni < 2.4 × 10-9). In addition, four novel sub-genome wide regions at 7p22.2, 7q22.1, 9p12 and 11q13.3 were identified (P < 5 × 10-7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines, and expression quantitative trait loci (eQTL) data highlighted candidate target genes for further investigation. CONCLUSION: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis. IMPACT: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.

5.
Int J Mol Sci ; 21(15)2020 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-32751388

RESUMO

Several studies support, both in vitro and in vivo, the anti-cancer effects of cannabidiol (CBD), a transient receptor potential vanilloid 2 (TRPV2) ligand. TRPV2, often dysregulated in tumors, is associated with altered cell proliferation and aggressiveness. Endometrial cancer (EC) is historically divided in type I endometrioid EC and type II non-endometrioid EC, associated with poor prognosis. Treatment options with chemotherapy and combinations with radiation showed only limited efficacy. Since no data are reported concerning TRPV2 expression as well as CBD potential effects in EC, the aim of this study was to evaluate the expression of TRPV2 in biopsies and cell lines as well as the effects of CBD in in vitro models. Overall survival (OS), progression-free survival (PFS), cell viability, migration, and chemo-resistance have been evaluated. Results show that TRPV2 expression increased with the malignancy of the cancer tissue and correlated with shorter PFS (p = 0.0224). Moreover, in vitro TRPV2 over-expression in Ishikawa cell line increased migratory ability and response to cisplatin. CBD reduced cell viability, activating predominantly apoptosis in type I cells and autophagy in mixed type EC cells. The CBD improved chemotherapeutic drugs cytotoxic effects, enhanced by TRPV2 over-expression. Hence, TRPV2 could be considered as a marker for optimizing the therapy and CBD might be a useful therapeutic option as adjuvant therapy.

6.
Front Oncol ; 9: 1073, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31681606

RESUMO

The programmed death-1 (PD-1, CD279) receptor with its ligands, programmed death ligand 1 (PD-L1, CD274, B7-H1), and programmed death ligand 2 (PD-L2, CD273, B7-DC), are the key players of one of the immune checkpoint pathways inhibiting T-cell activation. PD-L1 and PD-L2 are expressed in different cancer cells and their microenvironment, including infiltrating immune cells. However, their prognostic value is still debated and their role in the tumor microenvironment has not been fully elucidated yet. Considering the importance that cancer immunotherapy with anti-PD-1 and anti-PD-L1 antibodies gained in several tumor types, in this review article we aim to discuss the role of the PD-1/PD-L1/PD-L2 axis in gynecological cancers. PD-1 ligands have been detected in ovarian, cervical, vulvar and uterine cancers, and correlation with prognosis seems dependent from their distribution. About PD-L2, very few reports are available so far in gynecological malignancies, and its role is still not completely understood. Clinical trials using anti-PD-1 or anti-PD-L1 antibodies, but not anti-PD-L2, are currently ongoing, in all types of gynecological cancers. They have shown good safety profiles in a certain cohort of patients, but response rates remain low and many aspects remain controversial. In this review, we propose possible solutions to enhance the clinical efficacy of PD-1 axis targeting therapies. Regarding PD-L2, it might be useful to better clarify its role in order to improve the efficiency of immunotherapy in female malignancies.

7.
Methods Mol Biol ; 1862: 217-225, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30315470

RESUMO

In spite of the latest advancements in understanding cancer development and progression, drugs successful in preclinical testing often fail upon reaching phase III clinical trials. A reason for this is the use of inappropriate preclinical models that do not preserve tumor heterogeneity. Although used for decades, cell cultures derived from patients substantially deviate from their original biopsy upon culturing; moreover, they cannot predict the response of an organism as a whole.Patient-derived xenograft (PDX) models are emerging as powerful tools since they have a predictive therapeutic value and preserve the heterogeneity of the original tumors. PDX are established by implanting freshly isolated tumors from patients into immunocompromised mice, allowing for the progressive growth and amplification of cancer tissue for in vivo testing. Here, we describe the detailed methods we developed to establish PDX from both surgically removed endometrial cancer fragments (endometrial cancer) and fine-needle aspiration biopsies (pancreatic cancer).


Assuntos
Neoplasias do Endométrio/patologia , Neoplasias Pancreáticas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Criopreservação/instrumentação , Criopreservação/métodos , Neoplasias do Endométrio/cirurgia , Endométrio/patologia , Endométrio/cirurgia , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Feminino , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Pâncreas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto/instrumentação
8.
Gynecol Obstet Invest ; 83(6): 620-626, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30227411

RESUMO

In this brief report, we present our experience with 3-weekly paclitaxel-carboplatin chemotherapy for patients with vulvar cancer. Two patients with locally advanced disease had an impressive response allowing standard vulvar cancer surgery. One patient with metastatic disease had local stable disease though it was progressive in the lymph nodes. The available literature is sparse and retrospective. Based on promising results, however, a prospective multicenter study is mandatory in order to obtain full data in a larger series of patients in order to learn the benefits of neoadjuvant paclitaxel-carboplatin and compare the results with chemoradiation.


Assuntos
Carboplatina/administração & dosagem , Carcinoma de Células Escamosas/tratamento farmacológico , Paclitaxel/administração & dosagem , Neoplasias Vulvares/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia , Estudos Prospectivos , Estudos Retrospectivos , Resultado do Tratamento , Neoplasias Vulvares/patologia
9.
Int J Mol Sci ; 19(8)2018 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-30126113

RESUMO

Endometrial cancer (EC) is the most common malignancy of the genital tract among women in developed countries. Recently, a molecular classification of EC has been performed providing a system that, in conjunction with histological observations, reliably improves EC classification and enhances patient management. Patient-derived xenograft models (PDX) represent nowadays a promising tool for translational research, since they closely resemble patient tumour features and retain molecular and histological features. In EC, PDX models have already been used, mainly as an individualized approach to evaluate the efficacy of novel therapies and to identify treatment-response biomarkers; however, their uses in more global or holistic approaches are still missing. As a collaborative effort within the ENITEC network, here we describe one of the most extensive EC PDX cohorts developed from primary tumour and metastasis covering all EC subtypes. Our models are histologically and molecularly characterized and represent an excellent reservoir of EC tumour samples for translational research. This review compiles the information on current methods of EC PDX generation and their utility and provides new perspectives for the exploitation of these valuable tools in order to increase the success ratio for translating results to clinical practice.


Assuntos
Neoplasias do Endométrio/patologia , Endométrio/patologia , Animais , Modelos Animais de Doenças , Descoberta de Drogas/métodos , Neoplasias do Endométrio/tratamento farmacológico , Endométrio/efeitos dos fármacos , Feminino , Humanos , Transplante de Neoplasias/métodos , Medicina de Precisão/métodos , Pesquisa Médica Translacional/métodos , Transplante Heterólogo/métodos
10.
Int J Mol Sci ; 19(8)2018 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-30096949

RESUMO

Endometrial cancer is the most common type of cancer of the female reproductive tract. Although prognosis is generally good for patients with low-grade and early-stage diseases, the outcomes for high-grade and metastatic/recurrent cases remain poor, since traditional chemotherapy regimens based on platinum and taxanes have limited effects. No targeted agents have been approved so far, although several new drugs have been tested without striking results in clinical trials. Over the last decades, many efforts have been made towards the establishment and development of preclinical models, aiming at recapitulating the structural and molecular determinants of the disease. Here, we present an overview of the most commonly used in vitro and in vivo models and discuss their peculiar features, describing their main applications and the value in the advancement of both fundamental and translational endometrial cancer research.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Endométrio/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Pesquisa Médica Translacional , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Humanos , Terapia de Alvo Molecular , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , Taxoides/uso terapêutico
11.
Nat Commun ; 9(1): 3166, 2018 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-30093612

RESUMO

Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias do Endométrio/genética , Predisposição Genética para Doença , Alelos , Cromatina/química , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Fatores de Risco , Transdução de Sinais
12.
Cancer Med ; 7(5): 1978-1987, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29608257

RESUMO

Epidemiological, biological, and molecular data suggest links between endometriosis and endometrial cancer, with recent epidemiological studies providing evidence for an association between a previous diagnosis of endometriosis and risk of endometrial cancer. We used genetic data as an alternative approach to investigate shared biological etiology of these two diseases. Genetic correlation analysis of summary level statistics from genomewide association studies (GWAS) using LD Score regression revealed moderate but significant genetic correlation (rg  = 0.23, P = 9.3 × 10-3 ), and SNP effect concordance analysis provided evidence for significant SNP pleiotropy (P = 6.0 × 10-3 ) and concordance in effect direction (P = 2.0 × 10-3 ) between the two diseases. Cross-disease GWAS meta-analysis highlighted 13 distinct loci associated at P ≤ 10-5 with both endometriosis and endometrial cancer, with one locus (SNP rs2475335) located within PTPRD associated at a genomewide significant level (P = 4.9 × 10-8 , OR = 1.11, 95% CI = 1.07-1.15). PTPRD acts in the STAT3 pathway, which has been implicated in both endometriosis and endometrial cancer. This study demonstrates the value of cross-disease genetic analysis to support epidemiological observations and to identify biological pathways of relevance to multiple diseases.


Assuntos
Neoplasias do Endométrio/genética , Endometriose/genética , Predisposição Genética para Doença/genética , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Austrália/epidemiologia , Neoplasias do Endométrio/epidemiologia , Endometriose/epidemiologia , Endométrio/patologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único/genética , Fator de Transcrição STAT3/metabolismo
13.
Int J Cancer ; 142(6): 1230-1243, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29063609

RESUMO

Uterine leiomyosarcomas (uLMS) are rare, aggressive malignancies for which limited treatment options are available. To gain novel molecular insights into uLMS and identify potential novel therapeutic targets, we characterized 84 uLMS samples for genome-wide somatic copy number alterations, mutations, gene fusions and gene expression and performed a data integration analysis. We found that alterations affecting TP53, RB1, PTEN, MED12, YWHAE and VIPR2 were present in the majority of uLMS. Pathway analyses additionally revealed that the PI3K/AKT/mTOR, estrogen-mediated S-phase entry and DNA damage response signaling pathways, for which inhibitors have already been developed and approved, frequently harbored genetic changes. Furthermore, a significant proportion of uLMS was characterized by amplifications and overexpression of known oncogenes (CCNE1, TDO2), as well as deletions and reduced expression of tumor suppressor genes (PTEN, PRDM16). Overall, it emerged that the most frequently affected gene in our uLMS samples was VIPR2 (96%). Interestingly, VIPR2 deletion also correlated with unfavorable survival in uLMS patients (multivariate analysis; HR = 4.5, CI = 1.4-14.3, p = 1.2E-02), while VIPR2 protein expression was reduced in uLMS vs. normal myometrium. Moreover, stimulation of VIPR2 with its natural agonist VIP decreased SK-UT-1 uLMS cell proliferation in a dose-dependent manner. These data suggest that VIPR2, which is a negative regulator of smooth muscle cell proliferation, might be a novel tumor suppressor gene in uLMS. Our work further highlights the importance of integrative molecular analyses, through which we were able to uncover the genes and pathways most frequently affected by somatic alterations in uLMS.


Assuntos
Carcinogênese/genética , Leiomiossarcoma/genética , Receptores Tipo II de Peptídeo Intestinal Vasoativo/genética , Transdução de Sinais/genética , Neoplasias Uterinas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Estimativa de Kaplan-Meier , Leiomiossarcoma/mortalidade , Leiomiossarcoma/patologia , Leiomiossarcoma/terapia , Pessoa de Meia-Idade , Miométrio/patologia , Oncogenes/genética , Análise de Sequência de RNA/métodos , Neoplasias Uterinas/mortalidade , Neoplasias Uterinas/patologia , Neoplasias Uterinas/terapia , Sequenciamento Completo do Genoma/métodos
15.
Gynecol Oncol ; 146(3): 538-545, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28625393

RESUMO

OBJECTIVE: Uterine sarcomas (US) and carcinosarcomas (CS) are rare, aggressive cancers. The lack of reliable preclinical models hampers the search for new treatment strategies and predictive biomarkers. To this end, we established and characterized US and CS patient-derived xenograft (PDX) models. METHODS: Tumor fragments of US and CS were subcutaneously implanted into immunocompromised mice. Engrafted xenograft and original tumors were compared by means of histology, immunohistochemistry, whole-genome low-coverage sequencing for copy number variations, and RNA sequencing. RESULTS: Of 13 implanted leiomyosarcomas (LMS), 10 engrafted (engraftment rate of 77%). Also 2 out of 7 CS (29%) and one high-grade US (not otherwise specified) models were successfully established. LMS xenografts showed high histological similarity to their corresponding human tumors. Expression of desmin and/or H-caldesmon was detected in 8/10 LMS PDX models. We noticed that in CS models, characterized by the concomitant presence of a mesenchymal and an epithelial component, the relative distribution of the components is varying over the generations, as confirmed by changes in vimentin and cytokeratin expression. The similarity in copy number profiles between original and xenograft tumors ranged from 57.7% to 98.2% for LMS models and from 47.4 to 65.8% for CS models. Expression pattern stability was assessed by clustering RNA expression levels of original and xenograft tumors. Six xenografts clustered together with their original tumor, while 3 (all LMS) clustered apart. CONCLUSIONS: We present here a panel of clinically annotated uterine sarcoma and carcinosarcoma PDX models, which will be a useful tool for preclinical testing of new therapies.


Assuntos
Carcinossarcoma/patologia , DNA de Neoplasias/análise , Modelos Animais de Doenças , Xenoenxertos/patologia , Leiomiossarcoma/patologia , RNA Neoplásico/análise , Neoplasias Uterinas/patologia , Adulto , Idoso , Animais , Proteínas de Ligação a Calmodulina/análise , Carcinossarcoma/química , Carcinossarcoma/genética , Variações do Número de Cópias de DNA , Desmina/análise , Feminino , Expressão Gênica , Sobrevivência de Enxerto , Xenoenxertos/química , Humanos , Leiomiossarcoma/química , Leiomiossarcoma/genética , Camundongos , Pessoa de Meia-Idade , Transplante de Neoplasias , Análise de Sequência de RNA , Transplante Heterólogo , Neoplasias Uterinas/química , Neoplasias Uterinas/genética
16.
Clin Cancer Res ; 23(5): 1274-1285, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-28232476

RESUMO

Purpose: Uterine sarcomas are rare and heterogeneous tumors characterized by an aggressive clinical behavior. Their high rates of recurrence and mortality point to the urgent need for novel targeted therapies and alternative treatment strategies. However, no molecular prognostic or predictive biomarkers are available so far to guide choice and modality of treatment.Experimental Design: We investigated the expression of several druggable targets (phospho-S6S240 ribosomal protein, PTEN, PDGFR-α, ERBB2, and EGFR) in a large cohort of human uterine sarcoma samples (288), including leiomyosarcomas, low-grade and high-grade endometrial stromal sarcomas, undifferentiated uterine sarcomas, and adenosarcomas, together with 15 smooth muscle tumors of uncertain malignant potential (STUMP), 52 benign uterine stromal tumors, and 41 normal uterine tissues. The potential therapeutic value of the most promising target, p-S6S240, was tested in patient-derived xenograft (PDX) leiomyosarcoma models.Results: In uterine sarcomas and STUMPs, S6S240 phosphorylation (reflecting mTOR pathway activation) was associated with higher grade (P = 0.001) and recurrence (P = 0.019), as shown by logistic regression. In addition, p-S6S240 correlated with shorter progression-free survival (P = 0.034). Treatment with a dual PI3K/mTOR inhibitor significantly reduced tumor growth in 4 of 5 leiomyosarcoma PDX models (with tumor shrinkage in 2 models). Remarkably, the 4 responding models showed basal p-S6S240 expression, whereas the nonresponding model was scored as negative, suggesting a role for p-S6S240 in response prediction to PI3K/mTOR inhibition.Conclusions: Dual PI3K/mTOR inhibition represents an effective therapeutic strategy in uterine leiomyosarcoma, and p-S6S240 expression is a potential predictive biomarker for response to treatment. Clin Cancer Res; 23(5); 1274-85. ©2017 AACR.


Assuntos
Leiomiossarcoma/tratamento farmacológico , Proteína S6 Ribossômica/genética , Serina-Treonina Quinases TOR/genética , Neoplasias Uterinas/tratamento farmacológico , Animais , Biomarcadores Tumorais/genética , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Leiomiossarcoma/genética , Leiomiossarcoma/patologia , Camundongos , Terapia de Alvo Molecular , Fosfatidilinositol 3-Quinases/genética , Inibidores de Fosfoinositídeo-3 Quinase , Fosforilação , Prognóstico , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Nat Rev Cancer ; 17(4): 254-268, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28104906

RESUMO

Patient-derived xenografts (PDXs) have emerged as an important platform to elucidate new treatments and biomarkers in oncology. PDX models are used to address clinically relevant questions, including the contribution of tumour heterogeneity to therapeutic responsiveness, the patterns of cancer evolutionary dynamics during tumour progression and under drug pressure, and the mechanisms of resistance to treatment. The ability of PDX models to predict clinical outcomes is being improved through mouse humanization strategies and the implementation of co-clinical trials, within which patients and PDXs reciprocally inform therapeutic decisions. This Opinion article discusses aspects of PDX modelling that are relevant to these questions and highlights the merits of shared PDX resources to advance cancer medicine from the perspective of EurOPDX, an international initiative devoted to PDX-based research.


Assuntos
Neoplasias/terapia , Medicina de Precisão , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Biomarcadores Tumorais/análise , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Humanos , Imunoterapia , Camundongos , Metástase Neoplásica , Neoplasias/patologia , Células-Tronco Neoplásicas/fisiologia
18.
Anticancer Res ; 36(10): 5381-5384, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27798902

RESUMO

BACKGROUND/AIM: Human epidermal growth factor receptor 2 (HER2) positivity is associated with a worse prognosis in endometrial cancer (EC). Trastuzumab as a single agent did not demonstrate activity in such cases but there are no reports on its combined use with taxanes. We report the outcome in patients treated simultaneously with trastuzumab and paclitaxel for advanced or recurrent HER2-positive endometrial carcinoma and compared it to their microsatellite instability (MSI) status and PIK3CA mutational profiles. PATIENTS AND METHODS: Patients with advancedor recurrent endometrial carcinoma showing HER2 overexpression (2+ or 3+ immunohistochemical staining) or HER2 amplification (fluorescence in situ hybridization (FISH) HER2/chromosome 17 centromere (CEP 17) ratio >2.0) were treated with trastuzumab (8 mg/kg) and paclitaxel (90 mg/m2) every three weeks. Evaluation of the response was assessed according to the response evaluation criteria in solid tumors (RECIST) guidelines. Endometrial tumors, sampled before the beginning of trastuzumab, were genotyped for PIK3CA hot spot mutations using Sequenom iPLEX Assay technology. RESULTS: Two uterine serous adenocarcinomas and one grade 3 endometrioid adenocarcinoma showing HER2 positivity were treated with trastuzumab and paclitaxel. Between three and seven months of treatment, the three cases showed progressive disease. The genomic analysis of the three cases showed different mutational profiles. One case was found to have MSI and had one PIK3CA mutation. The two others showed no hot spot mutation for PIK3CA. CONCLUSION: Even associated with paclitaxel, HER2-positive endometrial carcinomas poorly responded to trastuzumab. This report underlines the low accuracy of HER2 positivity to predict response of endometrial cancer to combined targeted therapy using trastuzumab and paclitaxel.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Endométrio/tratamento farmacológico , Genes erbB-2 , Idoso , Neoplasias do Endométrio/genética , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Paclitaxel/administração & dosagem , Trastuzumab/administração & dosagem
19.
EMBO Rep ; 17(12): 1872-1889, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27852622

RESUMO

MYC deregulation is common in human cancer and has a role in sustaining the aggressive cancer stem cell populations. MYC mediates a broad transcriptional response controlling normal biological programmes, but its activity is not clearly understood. We address MYC function in cancer stem cells through the inducible expression of Omomyc-a MYC-derived polypeptide interfering with MYC activity-taking as model the most lethal brain tumour, glioblastoma. Omomyc bridles the key cancer stemlike cell features and affects the tumour microenvironment, inhibiting angiogenesis. This occurs because Omomyc interferes with proper MYC localization and itself associates with the genome, with a preference for sites occupied by MYC This is accompanied by selective repression of master transcription factors for glioblastoma stemlike cell identity such as OLIG2, POU3F2, SOX2, upregulation of effectors of tumour suppression and differentiation such as ID4, MIAT, PTEN, and modulation of the expression of microRNAs that target molecules implicated in glioblastoma growth and invasion such as EGFR and ZEB1. Data support a novel view of MYC as a network stabilizer that strengthens the regulatory nodes of gene expression networks controlling cell phenotype and highlight Omomyc as model molecule for targeting cancer stem cells.


Assuntos
Regulação Neoplásica da Expressão Gênica , Genes myc , Glioblastoma/genética , Células-Tronco Neoplásicas/fisiologia , Fragmentos de Peptídeos/genética , Proteínas Proto-Oncogênicas c-myc/genética , Fatores de Transcrição/genética , Inibidores da Angiogênese , Apoptose , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diferenciação Celular , Proliferação de Células , Receptores ErbB/genética , Glioblastoma/fisiopatologia , Humanos , Proteínas Inibidoras de Diferenciação/genética , MicroRNAs/genética , Proteínas do Tecido Nervoso/genética , Fator de Transcrição 2 de Oligodendrócitos , Ligação Proteica , Ativação Transcricional , Microambiente Tumoral/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética
20.
Cancer Epidemiol Biomarkers Prev ; 25(11): 1503-1510, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27550749

RESUMO

BACKGROUND: The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist-hip ratio (WHR) are associated with endometrial cancer risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and endometrial cancer in 6,609 cases and 37,926 country-matched controls. METHODS: Logistic regression analysis and fixed effects meta-analysis were used to test for associations between endometrial cancer risk and (i) individual BMI or WHR SNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for endometrial cancer was assessed using Mendelian randomization, with BMIwGRS as instrumental variable. RESULTS: The BMIwGRS was significantly associated with endometrial cancer risk (P = 3.4 × 10-17). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m2 of genetically predicted BMI was 2.06 [95% confidence interval (CI), 1.89-2.21], larger than the observed effect of BMI on endometrial cancer risk (OR = 1.55; 95% CI, 1.44-1.68, per 5 kg/m2). The association attenuated but remained significant after adjusting for BMI (OR = 1.22; 95% CI, 1.10-1.39; P = 5.3 × 10-4). There was evidence of directional pleiotropy (P = 1.5 × 10-4). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P < 4.0 × 10-4), independent of BMI. Endometrial cancer was not significantly associated with individual WHR SNPs or the WHRwGRS. CONCLUSIONS: BMI, but not WHR, is causally associated with endometrial cancer risk, with evidence that some BMI-associated SNPs alter endometrial cancer risk via mechanisms other than measurable BMI. IMPACT: The causal association between BMI SNPs and endometrial cancer has possible implications for endometrial cancer risk modeling. Cancer Epidemiol Biomarkers Prev; 25(11); 1503-10. ©2016 AACR.


Assuntos
Índice de Massa Corporal , Neoplasias do Endométrio/etiologia , Predisposição Genética para Doença , Análise da Randomização Mendeliana , Obesidade/complicações , Polimorfismo de Nucleotídeo Único , Neoplasias do Endométrio/genética , Feminino , Humanos , Obesidade/genética , Relação Cintura-Quadril
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