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1.
Mol Ther ; 24(8): 1492-501, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27203445

RESUMO

We have conducted a phase 1 study of intravenous vvDD, a Western Reserve strain oncolytic vaccinia virus, on 11 patients with standard treatment-refractory advanced colorectal or other solid cancers. The primary endpoints were maximum tolerated dose and associated toxicity while secondary endpoints were pharmacokinetics, pharmacodynamics, immune responses, and antitumor activity. No dose-limiting toxicities and treatment related severe adverse events were observed. The most common adverse events were grades 1/2 flu-like symptoms. Virus genomes were detectable in the blood 15-30 minutes after virus administration in a dose-dependent manner. There was evidence of a prolonged virus replication in tumor tissues in two patients, but no evidence of virus replication in non-tumor tissues, except a healed injury site and an oral thrush. Over 100-fold of anti-viral antibodies were induced in patients' sera. A strong induction of inflammatory and Th1, but not Th2 cytokines, suggested a potent Th1-mediated immunity against the virus and possibly the cancer. One patient showed a mixed response on PET-CT with resolution of some liver metastases, and another patient with cutaneous melanoma demonstrated clinical regression of some lesions. Given the confirmed safety, further trials evaluating intravenous vvDD in combination with therapeutic transgenes, immune checkpoint blockade or complement inhibitors, are warranted.


Assuntos
Terapia Genética , Vetores Genéticos/genética , Neoplasias/genética , Neoplasias/terapia , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Poxviridae/genética , Adulto , Idoso , Anticorpos Antivirais/imunologia , Terapia Combinada , Citocinas/metabolismo , Feminino , Vetores Genéticos/administração & dosagem , Vetores Genéticos/efeitos adversos , Vetores Genéticos/farmacocinética , Humanos , Mediadores da Inflamação , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias/diagnóstico , Neoplasias/mortalidade , Terapia Viral Oncolítica/efeitos adversos , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/imunologia , Poxviridae/imunologia , Retratamento , Resultado do Tratamento
2.
Ann Surg Oncol ; 23(2): 655-62, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26289805

RESUMO

BACKGROUND: Complement is a central part of both the innate and adaptive immune response and its activation has traditionally been considered part of the immunosurveillance response against cancer. Its pro-inflammatory role and its contribution to the development of many illnesses associated with inflammatory states implicate complement in carcinogenesis. METHODS: We evaluated the role of three protein inhibitors of complement-cobra venom factor, humanized cobra venom factor, and recombinant staphylococcus aureus superantigen-like protein 7-in the setting of a transplantable murine colon cancer model. Outcomes were evaluated by monitoring tumor growth, and flow cytometry, ELISPOT, and quantitative real-time PCR were used to determine the impact of complement inhibition on the host immune response. RESULTS: Complement inhibitors were effective at depleting complement component C3 in tumor bearing mice and this was temporally correlated with a decreased rate of tumor growth during the establishment of tumors. Treatment with cobra venom factor resulted in increased CD8(+) T cells as a percentage of tumor-infiltrating cells as well as a reduced immunosuppressive environment evidenced by decreased myeloid derived suppressor cells in splenocytes of treated mice. Complement inhibition resulted in increased expression of the chemoattractive cytokines CCL5, CXCL10, and CXCL11. DISCUSSION: Complement depletion represents a promising mode of immunotherapy in cancer by its ability to impair tumor growth by increasing the host's effective immune response to tumor and diminishing the immunosuppressive effect created by the tumor microenvironment and ultimately could be utilized as a component of combination immunotherapy.


Assuntos
Neoplasias do Colo/terapia , Ativação do Complemento/efeitos dos fármacos , Complemento C3/antagonistas & inibidores , Inativadores do Complemento/farmacologia , Imunoterapia , Animais , Western Blotting , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/imunologia , Neoplasias do Colo/metabolismo , Venenos Elapídicos/farmacologia , Ensaio de Imunoadsorção Enzimática , Exotoxinas/farmacologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Superantígenos/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Células Tumorais Cultivadas , Microambiente Tumoral/efeitos dos fármacos
3.
Mol Ther ; 23(1): 202-14, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25292189

RESUMO

Oncolytic viral therapy utilizes a tumor-selective replicating virus which preferentially infects and destroys cancer cells and triggers antitumor immunity. The Western Reserve strain of vaccinia virus (VV) is the most virulent strain of VV in animal models and has been engineered for tumor selectivity through two targeted gene deletions (vvDD). We performed the first-in-human phase 1, intratumoral dose escalation clinical trial of vvDD in 16 patients with advanced solid tumors. In addition to safety, we evaluated signs of vvDD replication and spread to distant tumors, pharmacokinetics and pharmacodynamics, clinical and immune responses to vvDD. Dose escalation proceeded without dose-limiting toxicities to a maximum feasible dose of 3 × 10(9) pfu. vvDD replication in tumors was reproducible. vvDD genomes and/or infectious particles were recovered from injected (n = 5 patients) and noninjected (n = 2 patients) tumors. At the two highest doses, vvDD genomes were detected acutely in blood in all patients while delayed re-emergence of vvDD genomes in blood was detected in two patients. Fifteen of 16 patients exhibited late symptoms, consistent with ongoing vvDD replication. In summary, intratumoral injection of the oncolytic vaccinia vvDD was well-tolerated in patients and resulted in selective infection of injected and noninjected tumors and antitumor activity.


Assuntos
Neoplasias da Mama/terapia , Neoplasias do Colo/terapia , Melanoma/terapia , Neoplasias Pancreáticas/terapia , Neoplasias Cutâneas/terapia , Vaccinia virus/imunologia , Replicação Viral/genética , Idoso , Animais , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Relação Dose-Resposta Imunológica , Feminino , Deleção de Genes , Humanos , Injeções Intralesionais , Masculino , Melanoma/imunologia , Melanoma/patologia , Pessoa de Meia-Idade , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/genética , Vírus Oncolíticos/crescimento & desenvolvimento , Vírus Oncolíticos/imunologia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Vaccinia virus/genética , Vaccinia virus/crescimento & desenvolvimento
4.
Mol Ther ; 21(5): 1024-33, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23439499

RESUMO

Oncolytic poxviruses have demonstrated initial promising results in patients with cancer in clinical trials, yet further improvements are needed. It has been shown that a single point mutation in the A34R gene resulted in the production of more total progeny virus and more extracellular enveloped virus (EEV), a form that can be immune-evasive and with enhanced spread. We have genetically engineered a new oncolytic poxvirus (designated vA34R) by incorporating this mutated A34R gene into a viral backbone (vvDD) which was designed for tumor-selective replication. This rationally designed virus can evade neutralization from antipoxvirus antibodies and is highly cytotoxic to cancer cells. It demonstrates improved spread and increased replication within the peritoneal cavity resulting in improved antitumor effects in a peritoneal carcinomatosis (PC) model of MC38 colon cancer. Impressively, after carrier cell-mediated delivery in the preimmunized host, vA34R displayed high replication in tumor nodules yet low accumulation in normal tissues thus enhancing the therapeutic index leading to 70% long-term cures. These results demonstrate that vA34R gains an enhanced therapeutic index for PC via immune evasion, increased spread, and production of more progeny virus. Thus, vA34R may be a potent oncolytic virus (OV) for patients with PC, even after prior exposure to vaccinia virus (VV).


Assuntos
Vetores Genéticos/fisiologia , Mutação , Vírus Oncolíticos/fisiologia , Poxviridae/fisiologia , Proteínas Virais/genética , Animais , Carcinoma/imunologia , Carcinoma/mortalidade , Carcinoma/terapia , Linhagem Celular Tumoral , Efeito Citopatogênico Viral , Modelos Animais de Doenças , Feminino , Técnicas de Transferência de Genes , Vetores Genéticos/administração & dosagem , Humanos , Camundongos , Terapia Viral Oncolítica , Neoplasias Peritoneais/imunologia , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/terapia , Infecções por Poxviridae/imunologia , Infecções por Poxviridae/virologia , Vaccinia virus/fisiologia , Replicação Viral
5.
J Surg Oncol ; 106(7): 911-7, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22585683

RESUMO

Pseudomyxoma peritonei (PMP) is characterized by intraperitoneal dissemination of mucinous ascites. This malignancy frequently recurs despite aggressive locoregional therapies, demonstrates chemo-insensitivity and lacks targeted therapies. This review addresses some intriguing questions in PMP; what role does mucin play in this malignancy?; what genetic alterations and dysregulated signaling pathways lead to a putative goblet cell-lineage differentiation or mucin overexpression?; are targeted therapies against known transcriptional pathways for mucin production a novel therapeutic strategy in this malignancy?


Assuntos
Mucinas/fisiologia , Neoplasias Peritoneais/etiologia , Neoplasias Peritoneais/patologia , Pseudomixoma Peritoneal/etiologia , Pseudomixoma Peritoneal/patologia , Células Caliciformes/fisiologia , Humanos , Neoplasias Peritoneais/terapia , Pseudomixoma Peritoneal/terapia , Transdução de Sinais/fisiologia
6.
Ann Surg Oncol ; 19(5): 1402-9, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22302271

RESUMO

BACKGROUND: Intraperitoneal accumulation of mucinous ascites in pseudomyxoma peritonei (PMP) promotes an inflammatory/fibrotic reaction that progresses to bowel obstruction and eventual patient demise. Cytokines and inflammation-associated transcription factor binding sites, such as glucocorticoid response elements and COX-2, regulate secretory mucin, specifically MUC2, production. We hypothesized that anti-inflammatory drugs targeting inflammation-associated pathways may reduce mucin production and subsequent disease morbidity in PMP. METHODS: The effects of dexamethasone and Celebrex were assessed in mucin-secreting human colon cancer LS174T cells in vitro and murine xenograft models of LS174T and human appendiceal PMP in vivo by serial parametric measurements, MUC2 transcripts via real-time RT-PCR, and MUC2 protein expression via immunofluorescence assays. RESULTS: Dexamethasone significantly inhibited basal MUC2 mRNA levels in LS174T cells, inhibited mucinous tumor accumulation in an intraperitoneal PMP xenograft model, and prolonged survival in a subcutaneous LS174T xenograft model. Celebrex significantly inhibited sodium butyrate-stimulated MUC2 mRNA levels in LS174T cells and demonstrated a statistically nonsignificant trend toward reduced mucinous tumor growth and prolonged survival in the xenograft models. MUC2 protein analysis by immunofluorescence demonstrated a dual effect of dexamethasone on mucin production and tumor cell count. CONCLUSIONS: Inflammatory mediators are known to regulate mucin production and may promote overexpression of MUC2 by neoplastic cells with goblet cell phenotype in PMP. Anti-inflammatory drugs, dexamethasone and Celebrex, could inhibit extracellular mucin production in PMP by targeting inflammatory cascades and, therefore, may decrease compressive symptoms, increase the disease-free interval, and reduce the extent or frequency of morbid cytoreductive surgeries.


Assuntos
Dexametasona/administração & dosagem , Mucina-2/biossíntese , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/metabolismo , Pseudomixoma Peritoneal/tratamento farmacológico , Pseudomixoma Peritoneal/metabolismo , Pirazóis/administração & dosagem , Sulfonamidas/administração & dosagem , Administração Oral , Animais , Anti-Inflamatórios/administração & dosagem , Neoplasias do Apêndice/química , Neoplasias do Apêndice/tratamento farmacológico , Neoplasias do Apêndice/metabolismo , Neoplasias do Apêndice/patologia , Celecoxib , Neoplasias do Colo/química , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Esquema de Medicação , Humanos , Camundongos , Camundongos Nus , Mucina-2/efeitos dos fármacos , Mucina-2/isolamento & purificação , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias Peritoneais/química , Neoplasias Peritoneais/patologia , Pseudomixoma Peritoneal/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Mol Cancer ; 10: 63, 2011 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-21609483

RESUMO

BACKGROUND: Homeobox genes murine Rhox5 and human RHOXF1 are expressed in early embryonic stages and then mostly restricted to germline tissues in normal adult, yet they are aberrantly expressed in cancer cells in vitro and in vivo . Here we study the epigenetic regulation and potential functions of Rhox5 gene. FINDINGS: In Rhox5-silenced or extremely low expresser cells, we observed low levels of active histone epigenetic marks (H3ac, H4ac and H3K4me2) and high levels of repressive mark H3K9me2 along with DNA hypermethylation in the promoter. In Rhox5 low expresser cells, we typically observed modest levels of both active and repressive histone marks along with moderate DNA methylation. In Rhox5 highly expressed CT26 cancer cells, we observed DNA hypomethylation along with high levels of both active and repressive histone marks. Epigenetic drugs (retinoic acid and MS-275) induced F9 cell differentiation with enhanced Rhox5 expression and dynamic changes of epigenetic marks. Finally, Rhox5 knockdown by small hairpin RNA (shRNA) in CT26 colon cancer decreased cell proliferation and migration in vitro and tumor growth in vivo . CONCLUSIONS: Both DNA methylation and histone methylation/acetylation play key roles in modulating Rhox5 expression in various cell types. The stem cell-like "bivalent domain", an epigenetic feature originally identified in key differentiation genes within stem cells, exists in the Rhox5 gene promoter in not only embryonic stem cells but also cancer cells, cancer stem cells, and differentiated Sertoli cells. As Ras signaling-dependent Rhox5 expression promotes tumor growth, Rhox5 may be an ideal target for therapeutic intervention in cancer.


Assuntos
Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Neoplasias/fisiopatologia , Células-Tronco/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Animais , Benzamidas/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/genética , Metilação de DNA/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Histonas/metabolismo , Humanos , Metilação/efeitos dos fármacos , Camundongos , Camundongos Nus , Regiões Promotoras Genéticas/genética , Piridinas/farmacologia , RNA Mensageiro/genética , Células-Tronco/metabolismo , Tretinoína/farmacologia , Carga Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Mol Pharmacol ; 76(5): 1072-81, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19679824

RESUMO

Epigenetic therapy of cancer using inhibitors of DNA methyltransferases (DNMT) or/and histone deacetylases (HDACs) has shown promising results in preclinical models and is being investigated in clinical trials. Homeodomain proteins play important roles in normal development and carcinogenesis. In this study, we demonstrated for the first time that an epigenetic drug could up-regulate homeobox genes in the reproductive homeobox genes on chromosome X (Rhox) family, including murine Rhox5, Rhox6, and Rhox9 and human RhoxF1 and RhoxF2 in breast, colon, and other types of cancer cells. We examined the molecular mechanisms underlining selective induction of Rhox5 in cancer cells by three epigenetic drugs: 5-aza-2'-deoxycytidine (DAC; decitabine), arsenic trioxide (ATO), and MS-275 [entinostat; N-(2-aminophenyl)-4-[N-(pyridine-3-ylmethoxy-carbonyl)aminomethyl]benzamide]. DAC induced Rhox5 mRNA expression from both distal promoter (Pd) and proximal promoter, whereas MS-275 and ATO induced gene expression from the Pd only. DAC and ATO inhibited both DNMT1 and DNMT3B protein expression, whereas MS-275 significantly reduced DNMT3B protein. In contrast to DAC, neither MS-275 nor ATO induced DNA demethylation on the Pd region. All three drugs led to enhanced acetylation of histones H3 and H4 at the promoter region. The occupancy of the activating histone mark dimethylated lysine 4 of H3 at Pd was enhanced by DAC and MS-275 but not ATO. Because they modulate gene expression with different potencies through shared and distinct epigenetic mechanisms, these epigenetic drugs may possess great potential in different applications for epigenetic therapy of cancer and other diseases.


Assuntos
Epigênese Genética/fisiologia , Genes Homeobox/fisiologia , Proteínas de Homeodomínio/biossíntese , Proteínas de Homeodomínio/genética , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética , Regulação para Cima/fisiologia , Animais , Trióxido de Arsênio , Arsenicais/farmacologia , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Benzamidas/farmacologia , Linhagem Celular Tumoral , Metilases de Modificação do DNA/antagonistas & inibidores , Decitabina , Epigênese Genética/efeitos dos fármacos , Genes Homeobox/efeitos dos fármacos , Inibidores do Crescimento/farmacologia , Inibidores de Histona Desacetilases , Humanos , Masculino , Camundongos , Óxidos/farmacologia , Piridinas/farmacologia , Regulação para Cima/efeitos dos fármacos
9.
Cancer Res ; 65(21): 9991-8, 2005 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-16267024

RESUMO

The ability of cancer cells to evade apoptosis may permit survival of a recombinant vaccinia lacking antiapoptotic genes in cancer cells compared with normal cells. We have explored the deletion of two vaccinia virus host range/antiapoptosis genes, SPI-1 and SPI-2, for their effects on the viral replication and their ability to induce cell death in infected normal and transformed cells in vitro. Indeed, in three paired normal and transformed cell types, the SPI-1 and SPI-2 gene-deleted virus (vSP) preferentially replicates in transformed cells or p53-null cells when compared with their normal counterparts. This selectivity may be derived from the fact that vSP-infected normal cells died faster than infected cancer cells. A fraction of infected cells died with evidence of necrosis as shown by both flow cytometry and detection of high-mobility group B1 protein released from necrotic cells into the culture supernatant. When administered to animals, vSP retains full ability to replicate in tumor tissues, whereas replication in normal tissues is greatly diminished. In a model of viral pathogenesis, mice treated with vSP survived substantially longer when compared with mice treated with the wild-type virus. The mutant virus vSP displayed significant antitumoral effects in an MC38 s.c. tumor model in both nude (P < 0.001) and immunocompetent mice (P < 0.05). We conclude that this recombinant vaccinia vSP shows promise for oncolytic virus therapy. Given its enhanced tumor selectivity, improved safety profile, and substantial oncolytic effects following systemic delivery in murine models, it should also serve as a useful vector for tumor-directed gene therapy.


Assuntos
Terapia Viral Oncolítica/métodos , Vaccinia virus/fisiologia , Animais , Apoptose/genética , Linhagem Celular Transformada , Linhagem Celular Tumoral , Feminino , Deleção de Genes , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Vaccinia virus/genética , Vaccinia virus/patogenicidade , Replicação Viral
10.
Ann Neurol ; 52(5): 662-5, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12402268

RESUMO

We examined whether a herpes simplex virus vector that expresses human proenkephalin could be used to attenuate nociception in a model of bone cancer pain in mice. Osteolytic sarcoma cells were implanted into the medullary space of the right femur, followed by a subcutaneous inoculation of a replication-defective herpes simplex virus vector expressing human proenkephalin (vector SHPE) or a lacZ-expressing control vector (vector SHZ). SHPE-inoculated mice demonstrated a significant, naltrexone-reversible decrease in pain-related behavior assessed during open-field motor activity. These results suggest that gene transfer with an enkephalin-expressing vector may be used to treat pain resulting from cancer in bone.


Assuntos
Neoplasias Ósseas/terapia , Encefalinas/genética , Terapia Genética , Vetores Genéticos , Osteossarcoma/terapia , Cuidados Paliativos/métodos , Precursores de Proteínas/genética , Simplexvirus/genética , Animais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C3H , Sarcoma Experimental/terapia
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