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1.
Apoptosis ; 23(2): 143-151, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29352443

RESUMO

Pituitary tumors are the most common primary intracranial neoplasms. Humanin (HN) and Rattin (HNr), a rat homolog of HN, are short peptides with a cytoprotective action. In the present study, we aimed to evaluate whether endogenous HNr plays an antiapoptotic role in pituitary tumor cells. Thus, we used RNA interference based on short-hairpin RNA (shRNA) targeted to HNr (shHNr). A plasmid including the coding sequences for shHNr and dTomato fluorescent reporter gene was developed (pUC-shHNr). Transfection of somatolactotrope GH3 cells with pUC-shHNr increased apoptosis, suggesting that endogenous HNr plays a cytoprotective role in pituitary tumor cells. In order to evaluate the effect of blockade of endogenous HNr expression in vivo, we constructed a recombinant baculovirus (BV) encoding shHNr (BV-shHNr). In vitro, BV-shRNA was capable of transducing more than 80% of GH3 cells and decreased HNr mRNA. Also, BV-shHNr increased apoptosis in transduced GH3 cells. Intratumor injection of BV-shHNr to nude mice bearing s.c. GH3 tumors increased the number of apoptotic cells, delayed tumor growth and enhanced survival rate, suggesting that endogenous HNr may be involved in pituitary tumor progression. These preclinical data suggests that the silencing of HN expression could have a therapeutic impact on the treatment of pituitary tumors.


Assuntos
Baculoviridae/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Hipofisárias/genética , Interferência de RNA , Animais , Apoptose/efeitos dos fármacos , Baculoviridae/genética , Linhagem Celular Tumoral , Feminino , Terapia Genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Camundongos Nus , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/terapia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Transdução Genética
2.
Breast Cancer Res Treat ; 166(2): 393-405, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28756536

RESUMO

PURPOSE: Regulatory T cells (Tregs) impair the clinical benefit of cancer immunotherapy. To optimize the antitumor efficacy of therapeutic dendritic cell (DC) vaccines, we aimed to inhibit Foxp3, a transcription factor required for Treg function. METHODS: Mice bearing established syngeneic LM3 and 4T1 breast tumors were treated with antitumor DC vaccines and a synthetic peptide (P60) that has been shown to inhibit Foxp3. RESULTS: Treatment with P60 improved the therapeutic efficacy of DC vaccines in these experimental models. In addition, monotherapy with P60 inhibited tumor growth in immunocompetent as well as in immuno-compromised animals bearing established tumors. We found expression of Foxp3 in human and murine breast tumor cells. P60 inhibited IL-10 secretion in breast cancer cells that expressed Foxp3. CONCLUSIONS: Our results suggest that Foxp3 blockade improves the therapeutic efficacy of DC vaccines by inhibition of Tregs and through a direct antitumor effect. This strategy could prove useful to neutralize the immunosuppressive microenvironment and to boost antitumor immunity in breast cancer.


Assuntos
Neoplasias da Mama/terapia , Peptídeos Penetradores de Células/administração & dosagem , Células Dendríticas/transplante , Fatores de Transcrição Forkhead/antagonistas & inibidores , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/farmacologia , Linhagem Celular Tumoral , Peptídeos Penetradores de Células/farmacologia , Células Dendríticas/imunologia , Feminino , Humanos , Imunoterapia , Camundongos , Linfócitos T Reguladores/imunologia , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Viruses ; 15(3)2023 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-36992317

RESUMO

We aimed to assess the potential of baculoviral vectors (BV) for brain cancer gene therapy. We compared them with adenoviral vectors (AdV), which are used in neuro-oncology, but for which there is pre-existing immunity. We constructed BVs and AdVs encoding fluorescent reporter proteins and evaluated their transduction efficiency in glioma cells and astrocytes. Naïve and glioma-bearing mice were intracranially injected with BVs to assess transduction and neuropathology. Transgene expression was also assessed in the brain of BV-preimmunized mice. While the expression of BVs was weaker than AdVs in murine and human glioma cell lines, BV-mediated transgene expression in patient-derived glioma cells was similar to AdV-mediated transduction and showed strong correlation with clathrin expression, a protein that interacts with the baculovirus glycoprotein GP64, mediating BV endocytosis. BVs efficiently transduced normal and neoplastic astrocytes in vivo, without apparent neurotoxicity. BV-mediated transgene expression was stable for at least 21 days in the brain of naïve mice, but it was significantly reduced after 7 days in mice systemically preimmunized with BVs. Our findings indicate that BVs efficiently transduce glioma cells and astrocytes without apparent neurotoxicity. Since humans do not present pre-existing immunity against BVs, these vectors may constitute a valuable tool for the delivery of therapeutic genes into the brain.


Assuntos
Baculoviridae , Neoplasias Encefálicas , Terapia Genética , Vetores Genéticos , Glioma , Baculoviridae/genética , Baculoviridae/imunologia , Neoplasias Encefálicas/terapia , Glioma/terapia , Animais , Camundongos , Linhagem Celular Tumoral , Humanos , Ratos , Camundongos Endogâmicos C57BL , Masculino , Transdução Genética , Astrócitos/virologia , Transgenes/genética
4.
Expert Opin Ther Targets ; 25(12): 1045-1060, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34904924

RESUMO

INTRODUCTION: Gliomas are stratified by the presence of a hotspot mutation in the enzyme isocitrate dehydrogenase genes (IDH1/2). While mutated IDH (mIDH) correlates with better prognosis, the role of this mutation in antitumor immunity and the response to immunotherapy is not completely understood. Understanding the relationship between the genetic features of these tumors and the tumor immune microenvironment (TIME) may help to develop appropriate therapeutic strategies. AREAS COVERED: In this review we discussed the available literature related to the potential role of IDH mutations as an immunotherapeutic target in gliomas and profiled the immune transcriptome of glioma biopsies. We aimed to shed light on the role of mIDH on the immunological landscape of the different subtypes of gliomas, taking into account the most recent WHO classification of tumors of the central nervous system (CNS). We also discussed different immunotherapeutic approaches to target mIDH tumors and to overcome their immunosuppressive microenvironment. EXPERT OPINION: Data presented here indicates that the TIME not only differs in association with IDH mutation status, but also within glioma subtypes, suggesting that the cellular context affects the overall effect of this genetic lesion. Thus, specific therapeutic combinations may help patients diagnosed with different glioma subtypes.


Assuntos
Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Glioma/genética , Glioma/patologia , Glioma/terapia , Humanos , Imunoterapia , Isocitrato Desidrogenase/genética , Mutação , Microambiente Tumoral/genética
5.
Front Mol Neurosci ; 14: 621831, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33790740

RESUMO

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in the adult population and it carries a dismal prognosis. Inefficient drug delivery across the blood brain barrier (BBB), an immunosuppressive tumor microenvironment (TME) and development of drug resistance are key barriers to successful glioma treatment. Since gliomas occur through sequential acquisition of genetic alterations, gene therapy, which enables to modification of the genetic make-up of target cells, appears to be a promising approach to overcome the obstacles encountered by current therapeutic strategies. Gene therapy is a rapidly evolving field with the ultimate goal of achieving specific delivery of therapeutic molecules using either viral or non-viral delivery vehicles. Gene therapy can also be used to enhance immune responses to tumor antigens, reprogram the TME aiming at blocking glioma-mediated immunosuppression and normalize angiogenesis. Nano-particles-mediated gene therapy is currently being developed to overcome the BBB for glioma treatment. Another approach to enhance the anti-glioma efficacy is the implementation of viro-immunotherapy using oncolytic viruses, which are immunogenic. Oncolytic viruses kill tumor cells due to cancer cell-specific viral replication, and can also initiate an anti-tumor immunity. However, concerns still remain related to off target effects, and therapeutic and transduction efficiency. In this review, we describe the rationale and strategies as well as advantages and disadvantages of current gene therapy approaches against gliomas in clinical and preclinical studies. This includes different delivery systems comprising of viral, and non-viral delivery platforms along with suicide/prodrug, oncolytic, cytokine, and tumor suppressor-mediated gene therapy approaches. In addition, advances in glioma treatment through BBB-disruptive gene therapy and anti-EGFRvIII/VEGFR gene therapy are also discussed. Finally, we discuss the results of gene therapy-mediated human clinical trials for gliomas. In summary, we highlight the progress, prospects and remaining challenges of gene therapies aiming at broadening our understanding and highlighting the therapeutic arsenal for GBM.

6.
Expert Opin Ther Targets ; 24(11): 1121-1133, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32896197

RESUMO

Introduction: Prolactin (PRL) and its receptor (PRLR) have been associated with the development of hormone-dependent tumors and have been detected in glioblastoma (GBM) biopsies. GBM is the most common and aggressive primary brain tumor in adults and the prognosis for patients is dismal; hence researchers are exploring the PRLR pathway as a therapeutic target in this disease. Areas covered: This paper explores the effects of PRLR activation on the biology of GBM, the correlation between PRL and PRLR expression and GBM progression and survival in male and female patients. Finally, we discuss how a better understanding of the PRLR pathway may allow the development of novel treatments for GBM. Expert opinion: We propose PRL and PRLR as potential prognosis biomarkers and therapeutic targets in GBM. Local administration of PRLR inhibitors using gene therapy may offer a beneficial strategy for targeting GBM cells disseminated in the non-neoplastic brain; however, efficacy and safety require careful and extensive evaluation. The data depicted herein underline the need to (i) improve our understanding of sexual dimorphism in GBM, and (ii) develop accurate preclinical models that take into consideration different hormonal contexts, specific genetic alterations, and tumor grades.


Assuntos
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Receptores da Prolactina/metabolismo , Adulto , Animais , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/patologia , Feminino , Terapia Genética/métodos , Glioblastoma/patologia , Humanos , Masculino , Terapia de Alvo Molecular , Prognóstico , Prolactina/metabolismo
7.
Expert Opin Biol Ther ; 20(3): 305-317, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31959027

RESUMO

Introduction: The field of neuro-oncology has experienced significant advances in recent years. More is known now about the molecular and genetic characteristics of glioma than ever before. This knowledge leads to the understanding of glioma biology and pathogenesis, guiding the development of targeted therapeutics and clinical trials. The goal of this review is to describe the state of basic, translational, and clinical research as it pertains to biological and synthetic pharmacotherapy for gliomas.Areas covered: Challenges remain in designing accurate preclinical models and identifying patients that are likely to respond to a particular targeted therapy. Preclinical models for therapeutic assessment are critical to identify the most promising treatment approaches.Expert opinion: Despite promising new therapeutics, there have been no significant breakthroughs in glioma treatment and patient outcomes. Thus, there is an urgent need to better understand the mechanisms of treatment resistance and to design effective clinical trials.


Assuntos
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/imunologia , Vacinas Anticâncer/uso terapêutico , Terapia Genética , Glioblastoma/tratamento farmacológico , Glioblastoma/imunologia , Humanos , Imunoterapia Adotiva , Isocitrato Desidrogenase/antagonistas & inibidores , Isocitrato Desidrogenase/metabolismo , Nanomedicina , Terapia Viral Oncolítica
8.
Immunotherapy ; 10(4): 317-339, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29421984

RESUMO

There is a large unmet need for effective therapeutic approaches for glioma, the most malignant brain tumor. Clinical and preclinical studies have enormously expanded our knowledge about the molecular aspects of this deadly disease and its interaction with the host immune system. In this review we highlight the wide array of immunotherapeutic interventions that are currently being tested in glioma patients. Given the molecular heterogeneity, tumor immunoediting and the profound immunosuppression that characterize glioma, it has become clear that combinatorial approaches targeting multiple pathways tailored to the genetic signature of the tumor will be required in order to achieve optimal therapeutic efficacy.


Assuntos
Neoplasias Encefálicas/terapia , Glioma/terapia , Imunoterapia/métodos , Encéfalo/imunologia , Neoplasias Encefálicas/imunologia , Glioma/imunologia , Humanos , Imunoterapia/tendências
9.
Expert Opin Biol Ther ; 17(7): 797-812, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28446053

RESUMO

INTRODUCTION: Breast cancer is the most common cancer as well as the first cause of death by cancer in women worldwide. Although routine treatment improves the outcome of early stage breast cancer patients, there is no effective therapy for the disseminated disease. Immunotherapy has emerged as a powerful therapeutic strategy for the treatment of many cancers. Although traditionally conceived as a non-immunogenic tumor, breast cancer is now considered a potential target for immunotherapy. Areas covered: In this review, the authors discuss different immunotherapeutic strategies that are currently being tested for the treatment of breast cancer: These strategies include: (i) blockade of immunological checkpoints, (ii) antitumor vaccines, (iii) regulatory T cell blockade, (iv) adoptive T cell transfer therapy, (iv) adoptive immunotherapy with monoclonal antibodies, and (v) combination of immunotherapy with chemotherapy. Expert opinion: A growing body of evidence indicates that immunotherapeutic strategies can benefit a larger cohort of breast cancer patients than hitherto anticipated. Since breast tumors entail multiple mechanisms to impair antitumor immunity, the immunological characterization of individual tumors and the selection of suitable combinations of chemotherapeutic and immunotherapeutic approaches are required to achieve significant clinical benefit in these patients.


Assuntos
Neoplasias da Mama/terapia , Imunoterapia , Anticorpos Monoclonais/uso terapêutico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Antígeno CTLA-4/imunologia , Antígeno CTLA-4/metabolismo , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Terapia Combinada , Feminino , Humanos , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
10.
Expert Opin Biol Ther ; 17(8): 945-959, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28604109

RESUMO

INTRODUCTION: Breast cancer is the most common cancer in women all over the world. Furthermore, up to one third of breast tumors develop metastases that are resistant to standard therapies. Gene therapeutic strategies have been developed in order to specifically target cancer cells either directly or through the stimulation of antitumor immunity. Areas covered: This review describes the therapeutic strategies that are currently under development to treat this disease using engineered viral vectors including: adenovirus, adeno-associated virus, lentivirus, poxvirus, reovirus, baculovirus, herpesvirus and oncolytic viruses. Advantages and disadvantages of these multiple gene therapy platforms are discussed in detail. Expert opinion: Metastatic breast cancer is a perfect candidate for gene therapy approaches due to the presence of several tumor antigens and the aberrant expression of many molecular pathways. Oncolytic vectors are able to attack tumor cells while sparing normal cells and their activity is often enhanced by the administration of chemotherapy. However, more efforts are needed in order to reduce toxicity and to achieve better transduction efficiency. Improved preclinical models and a more critical patient selection for clinical trials, along with advances in gene therapy regulations, will surely facilitate the evolution of gene therapy for the treatment of metastatic breast cancer.


Assuntos
Neoplasias da Mama/terapia , Terapia Viral Oncolítica , Adenoviridae/genética , Feminino , Vetores Genéticos/genética , Vetores Genéticos/metabolismo , Humanos , Lentivirus/genética , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/virologia , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/virologia , Vírus Oncolíticos/genética , Poxviridae/genética
11.
Expert Opin Biol Ther ; 17(5): 543-554, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28286975

RESUMO

INTRODUCTION: Malignant gliomas are highly invasive tumors, associated with a dismal survival rate despite standard of care, which includes surgical resection, radiotherapy and chemotherapy with temozolomide (TMZ). Precision immunotherapies or combinations of immunotherapies that target unique tumor-specific features may substantially improve upon existing treatments. Areas covered: Clinical trials of single immunotherapies have shown therapeutic potential in high-grade glioma patients, and emerging preclinical studies indicate that combinations of immunotherapies may be more effective than monotherapies. In this review, the authors discuss emerging combinations of immunotherapies and compare efficacy of single vs. combined therapies tested in preclinical brain tumor models. Expert opinion: Malignant gliomas are characterized by a number of factors which may limit the success of single immunotherapies including inter-tumor and intra-tumor heterogeneity, intrinsic resistance to traditional therapies, immunosuppression, and immune selection for tumor cells with low antigenicity. Combination of therapies which target multiple aspects of tumor physiology are likely to be more effective than single therapies. While a limited number of combination immunotherapies are described which are currently being tested in preclinical and clinical studies, the field is expanding at an astounding rate, and endless combinations remain open for exploration.


Assuntos
Neoplasias Encefálicas/terapia , Vacinas Anticâncer/administração & dosagem , Terapia Genética/métodos , Glioma/terapia , Imunoterapia/métodos , Animais , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/imunologia , Terapia Combinada/métodos , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Glioma/diagnóstico , Glioma/imunologia , Humanos , Temozolomida
12.
Expert Opin Biol Ther ; 16(10): 1245-64, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27411023

RESUMO

INTRODUCTION: Outcome for glioma (GBM) remains dismal despite advances in therapeutic interventions including chemotherapy, radiotherapy and surgical resection. The overall survival benefit observed with immunotherapies in cancers such as melanoma and prostate cancer has fuelled research into evaluating immunotherapies for GBM. AREAS COVERED: Preclinical studies have brought a wealth of information for improving the prognosis of GBM and multiple clinical studies are evaluating a wide array of immunotherapies for GBM patients. This review highlights advances in the development of immunotherapeutic approaches. We discuss the strategies and outcomes of active and passive immunotherapies for GBM including vaccination strategies, gene therapy, check point blockade and adoptive T cell therapies. We also focus on immunoediting and tumor neoantigens that can impact the efficacy of immunotherapies. EXPERT OPINION: Encouraging results have been observed with immunotherapeutic strategies; some clinical trials are reaching phase III. Significant progress has been made in unraveling the molecular and genetic heterogeneity of GBM and its implications to disease prognosis. There is now consensus related to the critical need to incorporate tumor heterogeneity into the design of therapeutic approaches. Recent data also indicates that an efficacious treatment strategy will need to be combinatorial and personalized to the tumor genetic signature.


Assuntos
Glioblastoma/imunologia , Glioblastoma/terapia , Glioma/imunologia , Glioma/terapia , Imunoterapia/tendências , Animais , Previsões , Terapia Genética/métodos , Terapia Genética/tendências , Glioblastoma/diagnóstico , Glioma/diagnóstico , Humanos , Imunização Passiva/métodos , Imunização Passiva/tendências , Imunoterapia/métodos , Prognóstico , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
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