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2.
Oncol Rep ; 45(2): 776-785, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33416143

RESUMO

Liver cancer (LC) is an aggressive disease with a markedly poor prognosis. Therapeutic options are limited, and, until recently the only FDA­approved agent for first­line treatment of patients with LC was the multi­kinase inhibitor sorafenib, which exhibits limited activity and an increased overall survival (OS) of only 3 months over placebo. Therefore, the development of alternative therapeutic molecules for the treatment of LC is an urgent medical need. Antibody­drug conjugates (ADCs) are an emerging class of novel anticancer agents, which have been developed recently for the treatment of malignant conditions, including LC, and are being studied in preclinical and clinical settings. Our group has recently generated an ADC [EV20/monomethyl auristatin F (MMAF)] by coupling the HER3 targeting antibody (EV20) to MMAF via a non­cleavable maleimidocaproyl linker. This ADC was revealed to possess potent therapeutic activity in melanoma and breast carcinoma. In the present study, using western blot and flow cytometric analysis, it was reported that HER­3 receptor was highly expressed in LC and activated by its ligand NRG­1ß in a panel of LC cell lines, thus indicating that this receptor may serve as a suitable target for ADC therapy. A novel ADC [EV20­sss­valine­citrulline (vc)/MMAF] was generated, in which the cytotoxic payload MMAF was site­specifically coupled to an engineered variant of EV20 via a vc cleavable linker. Cytotoxicity assays were performed to investigate in vitro antitumor activity of EV20­sss­vc/MMAF and it was compared to EV20/MMAF, which revealed only modest activity in LC.EV20­sss­vc/MMAF exhibited a significant cell killing activity in several LC cell lines. Additionally, in vivo xenograft experiments revealed that EV20­sss­vc/MMAF inhibited growth of LC tumors. The present data indicated that EV20­sss­vc/MMAF is a worthy candidate for the treatment of HER­3 positive LC.


Assuntos
Imunoconjugados/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Oligopeptídeos/farmacologia , Receptor ErbB-3/antagonistas & inibidores , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Imunoconjugados/uso terapêutico , Fígado/patologia , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Oligopeptídeos/uso terapêutico , Receptor ErbB-3/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Cancers (Basel) ; 12(10)2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33076448

RESUMO

Neuroblastoma is the most common extra-cranial solid tumor in infants and children, which accounts for approximately 15% of all cancer-related deaths in the pediatric population. New therapeutic modalities are urgently needed. Antibody-Drug Conjugates (ADC)s-based therapy has been proposed as potential strategy to treat this pediatric malignancy. LGALS3BP is a highly glycosylated protein involved in tumor growth and progression. Studies have shown that LGALS3BP is enriched in extracellular vesicles (EV)s derived by most neuroblastoma cells, where it plays a critical role in preparing a favorable tumor microenvironment (TME) through direct cross talk between cancer and stroma cells. Here, we describe the development of a non-internalizing LGALS3BP ADC, named 1959-sss/DM3, which selectively targets LGALS3BP expressing neuroblastoma. 1959-sss/DM3 mediated potent therapeutic activity in different types of neuroblastoma models. Notably, we found that treatments were well tolerated at efficacious doses that were fully curative. These results offer preclinical proof-of-concept for an ADC targeting exosomal LGALS3BP approach for neuroblastomas.

4.
J Control Release ; 277: 48-56, 2018 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-29550398

RESUMO

Cutaneous melanoma is one of the cancers with the fastest rising incidence and in its advanced metastatic form is a highly lethal disease. Despite the recent approval of several new drugs, the 5-year overall survival rate for advanced cutaneous melanoma is still below 20% and therefore, the development of novel treatments remains a primary need. Antibody-Drug Conjugates are an emerging novel class of anticancer agents, whose preclinical and clinical development has recently seen a remarkable increase in different tumors, including melanoma. Here, we have coupled the anti-HER-3 internalizing antibody EV20 to the cytotoxic drug monomethyl auristatin F (MMAF) to form a novel antibody-drug conjugate (EV20/MMAF). In a panel of human melanoma cell lines, this novel ADC shows a powerful, specific and target-dependent cell killing activity, independently of BRAF status. Efficacy studies demonstrated that a single administration of EV20/MMAF leads to a long-lasting tumor growth inhibition. Remarkably, the effect of this novel ADC was superior to the BRAF inhibitor vemurafenib in preventing kidney, liver and lung melanoma metastases. Overall, these results highlight EV20/MMAF as a novel ADC with promising therapeutic efficacy, warranting extensive pre-clinical evaluation in melanoma with high levels of HER-3 expression.


Assuntos
Aminobenzoatos/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Citotoxinas/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Imunoconjugados/administração & dosagem , Melanoma/tratamento farmacológico , Oligopeptídeos/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , Aminobenzoatos/metabolismo , Animais , Anticorpos Monoclonais/metabolismo , Linhagem Celular Tumoral , Citotoxinas/metabolismo , Relação Dose-Resposta a Droga , Humanos , Imunoconjugados/metabolismo , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Oligopeptídeos/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Melanoma Maligno Cutâneo
5.
Oncotarget ; 6(19): 16902-11, 2015 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-26160848

RESUMO

Approximately 5-10% of metastatic colorectal cancers harbor a BRAF-V600E mutation, which is correlated with resistance to EGFR-targeted therapies and worse clinical outcome. Vice versa, targeted inhibition of BRAF-V600E with the selective inhibitor PLX 4032 (Vemurafenib) is severely limited due to feedback re-activation of EGFR in these tumors. Mounting evidence indicates that upregulation of the ErbB-3 signaling axis may occur in response to several targeted therapeutics, including Vemurafenib, and NRG-1ß-dependent re-activation of the PI3K/AKT survival pathway has been associated with therapy resistance.Here we show that colon CSCs express, next to EGFR and ErbB-2, also significant amounts of ErbB-3 on their membrane. This expression is functional as NRG-1ß strongly induces AKT/PKB and ERK phosphorylation, cell proliferation, clonogenic growth and promotes resistance to Vemurafenib in BRAF-V600E mutant colon CSCs. This resistance was completely dependent on ErbB-3 expression, as evidenced by knockdown of ErbB-3. More importantly, resistance could be alleviated with therapeutic antibody blocking ErbB-3 activation, which impaired NRG-1ß-driven AKT/PKB and ERK activation, clonogenic growth in vitro and tumor growth in xenograft models. In conclusion, our findings suggest that targeting ErbB-3 receptors could represent an effective therapeutic approach in BRAF-V600E mutant colon cancer.


Assuntos
Neoplasias do Colo/patologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Células-Tronco Neoplásicas/metabolismo , Neuregulina-1/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Receptor ErbB-3/metabolismo , Animais , Antineoplásicos/farmacologia , Proliferação de Células , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Indóis/farmacologia , Camundongos , Camundongos Nus , Células-Tronco Neoplásicas/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sulfonamidas/farmacologia , Vemurafenib , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Hum Mutat ; 36(8): 787-96, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25952305

RESUMO

Noonan syndrome (NS) is a relatively common developmental disorder with a pleomorphic phenotype. Mutations causing NS alter genes encoding proteins involved in the RAS-MAPK pathway. We and others identified Casitas B-lineage lymphoma proto-oncogene (CBL), which encodes an E3-ubiquitin ligase acting as a tumor suppressor in myeloid malignancies, as a disease gene underlying a condition clinically related to NS. Here, we further explored the spectrum of germline CBL mutations and their associated phenotype. CBL mutation scanning performed on 349 affected subjects with features overlapping NS and no mutation in NS genes allowed the identification of five different variants with pathological significance. Among them, two splice-site changes, one in-frame deletion, and one missense mutation affected the RING domain and/or the adjacent linker region, overlapping cancer-associated defects. A novel nonsense mutation generating a v-Cbl-like protein able to enhance signal flow through RAS was also identified. Genotype-phenotype correlation analysis performed on available records indicated that germline CBL mutations cause a variable phenotype characterized by a relatively high frequency of neurological features, predisposition to juvenile myelomonocytic leukemia, and low prevalence of cardiac defects, reduced growth, and cryptorchidism. Finally, we excluded a major contribution of two additional members of the CBL family, CBLB and CBLC, to NS and related disorders.


Assuntos
Variação Genética , Mutação em Linhagem Germinativa , Proteínas Proto-Oncogênicas c-cbl/genética , Pré-Escolar , Feminino , Estudos de Associação Genética , Humanos , Masculino , Síndrome de Noonan/genética , Síndrome de Noonan/fisiopatologia , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-cbl/metabolismo
7.
J Proteome Res ; 13(4): 2120-36, 2014 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-24597989

RESUMO

p63 is an important regulator of epithelial development expressed in different variants containing (TA) or lacking (ΔN) the N-terminal transactivation domain. The different isoforms regulate stem-cell renewal and differentiation as well as cell senescence. Several studies indicate that p63 isoforms also play a role in cancer development; however, very little is known about the role played by p63 in regulating the cancer stem phenotype. Here we investigate the cellular signals regulated by TAp63 and ΔNp63 in a model of epithelial cancer stem cells. To this end, we used colon cancer stem cells, overexpressing either TAp63 or ΔNp63 isoforms, to carry out a proteomic study by chemical-labeling approach coupled to network analysis. Our results indicate that p63 is implicated in a wide range of biological processes, including metabolism. This was further investigated by a targeted strategy at both protein and metabolite levels. The overall data show that TAp63 overexpressing cells are more glycolytic-active than ΔNp63 cells, indicating that the two isoforms may regulate the key steps of glycolysis in an opposite manner. The mass-spectrometry proteomics data of the study have been deposited to the ProteomeXchange Consortium ( http://proteomecentral.proteomexchange.org ) via the PRIDE partner repository with data set identifiers PXD000769 and PXD000768.


Assuntos
Células-Tronco Neoplásicas/metabolismo , Mapas de Interação de Proteínas/fisiologia , Isoformas de Proteínas/metabolismo , Transdução de Sinais/fisiologia , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Humanos , Marcação por Isótopo , Metabolômica , Células-Tronco Neoplásicas/fisiologia , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Isoformas de Proteínas/química , Proteoma/análise , Proteoma/metabolismo , Proteômica , Fatores de Transcrição/química , Proteínas Supressoras de Tumor/química
8.
J Environ Manage ; 115: 136-46, 2013 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-23246906

RESUMO

Water resource management is often characterized by conflicts, as a result of the heterogeneity of interests associated with a shared resource. Many water conflicts arise on a global scale and, in particular, an increasing level of conflicts can be observed in the Mediterranean basin, characterized by water scarcity. In the present work, in order to assist the conflict analysis process, and thus outline a proper groundwater management, stakeholders were involved in the process and suitable tools were used in a Mediterranean area (the Apulia region, in Italy). In particular, this paper seeks to elicit and structure farmers' mental models influencing their decision over the main water source for irrigation. The more crucial groundwater is for farmers' objectives, the more controversial is the groundwater protection strategy. Bayesian Belief Networks were developed to simulate farmers' behavior with regard to groundwater management and to assess the impacts of protection strategy. These results have been used to calculate the conflict degree in the study area, derived from the introduction of policies for the reduction of groundwater exploitation for irrigation purposes. The less acceptable the policy is, the more likely it is that conflict will develop between farmers and the Regional Authority. The results of conflict analysis were also used to contribute to the debate concerning potential conflict mitigation measures. The approach adopted in this work has been discussed with a number of experts in groundwater management policies and irrigation management, and its main strengths and weaknesses have been identified. Increasing awareness of the existence of potential conflicts and the need to deal with them can be seen as an interesting initial shift in the Apulia region's water management regime, which is still grounded in merely technical approaches.


Assuntos
Água Subterrânea , Modelos Teóricos , Teorema de Bayes , Sistemas de Informação Geográfica
10.
Ann Neurol ; 54(1): 30-7, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12838518

RESUMO

DCX mutations cause mental retardation in male subjects with lissencephalypachygyria and in female subjects with subcortical band heterotopia (SBH). We observed four families in which carrier women had normal brain magnetic resonance imaging (MRI) and mild mental retardation, with or without epilepsy. Affected male subjects had SBH or pachygyria-SBH. In two families, the phenotype was mild in both genders. In the first family, we found a tyr138his mutation that is predicted to result in abnormal folding in the small hinge region. In the second family, we found an arg178cys mutation at the initial portion of R2, in the putative beta-sheet structure. Carrier female subjects with normal MRI showed no somatic mosaicism or altered X-inactivation in lymphocytes, suggesting a correlation between mild mutations and phenotypes. In the two other families, with severely affected boys, we found arg76ser and arg56gly mutations within the R1 region that are predicted to affect DCX folding, severely modifying its activity. Both carrier mothers showed skewed X-inactivation, possibly explaining their mild phenotypes. Missense DCX mutations may manifest as non-syndromic mental retardation with cryptogenic epilepsy in female subjects and SBH in boys. Mutation analysis in mothers of affected children is mandatory, even when brain MRI is normal.


Assuntos
Encefalopatias/genética , Coristoma/genética , Epilepsia/complicações , Epilepsia/genética , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Proteínas Associadas aos Microtúbulos , Neuropeptídeos/genética , Mutação Puntual/genética , Adolescente , Adulto , Encefalopatias/patologia , Análise Mutacional de DNA , Mecanismo Genético de Compensação de Dose , Proteínas do Domínio Duplacortina , Proteína Duplacortina , Feminino , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Linhagem , Polimorfismo Genético/genética , Índice de Gravidade de Doença
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