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1.
PLoS Pathog ; 15(8): e1007993, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31465513

RESUMO

Chikungunya virus (CHIKV) is an arthritogenic alphavirus that acutely causes fever as well as severe joint and muscle pain. Chronic musculoskeletal pain persists in a substantial fraction of patients for months to years after the initial infection, yet we still have a poor understanding of what promotes chronic disease. While replicating virus has not been detected in joint-associated tissues of patients with persistent arthritis nor in various animal models at convalescent time points, viral RNA is detected months after acute infection. To identify the cells that might contribute to pathogenesis during this chronic phase, we developed a recombinant CHIKV that expresses Cre recombinase (CHIKV-3'-Cre). CHIKV-3'-Cre replicated in myoblasts and fibroblasts, and it induced arthritis during the acute phase in mice. Importantly, it also induced chronic disease, including persistent viral RNA and chronic myositis and synovitis similar to wild-type virus. CHIKV-3'-Cre infection of tdTomato reporter mice resulted in a population of tdTomato+ cells that persisted for at least 112 days. Immunofluorescence and flow cytometric profiling revealed that these tdTomato+ cells predominantly were myofibers and dermal and muscle fibroblasts. Treatment with an antibody against Mxra8, a recently defined host receptor for CHIKV, reduced the number of tdTomato+ cells in the chronic phase and diminished the levels of chronic viral RNA, implicating these tdTomato+ cells as the reservoir of chronic viral RNA. Finally, isolation and flow cytometry-based sorting of the tdTomato+ fibroblasts from the skin and ankle and analysis for viral RNA revealed that the tdTomato+ cells harbor most of the persistent CHIKV RNA at chronic time points. Therefore, this CHIKV-3'-Cre and tdTomato reporter mouse system identifies the cells that survive CHIKV infection in vivo and are enriched for persistent CHIKV RNA. This model represents a useful tool for studying CHIKV pathogenesis in the acute and chronic stages of disease.

2.
Sci Rep ; 9(1): 9130, 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31235758

RESUMO

BYL719 is a PI3K inhibitor that has demonstrated efficacy in the treatment of head and neck squamous cell carcinoma. BYL719 exerts its therapeutic effect by suppressing AKT and other proliferative signaling mechanisms. Despite PI3K inhibition and AKT suppression, residual activity of protein S6, a core marker of proliferative activation, has been observed. HER3, either via dimerization or activation by its ligand neurgeulin (NRG), is known to activate PI3K. Thus, we hypothesized that co-targeting HER3 and PI3K would lead to greater suppression of the PI3K-AKT signaling pathway and greater tumor suppression than with BYL719 alone. We investigated biochemical expression and activation of the HER3-PI3K-AKT-S6 pathway in HNSCC cell lines and patient-derived xenografts (PDXs). Antitumor effects of HER3 and PI3K inhibitors alone and in combination were evaluated in cell culture and murine models. Treatment of HNSCC cell lines with BYL719 significantly reduced AKT activation and suppressed tumor growth. However, S6 was persistently activated despite suppression of AKT. Combination treatment with KTN3379, a monoclonal antibody targeted against HER3, and BYL719 led to enhanced suppression of in vitro and in vivo cancer growth and durable suppression of AKT and S6. Therefore, inhibition of HER3 with KTN3379 enhanced the effects of PI3K inhibition in pre-clinical HNSCC models. These data support co-targeting HER3 and PI3K for the treatment of HSNCC.

3.
J Exp Med ; 216(2): 419-427, 2019 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-30683736

RESUMO

PIK3CA is the most commonly altered oncogene in head and neck squamous cell carcinoma (HNSCC). We evaluated the impact of nonsteroidal anti-inflammatory drugs (NSAIDs) on survival in a PIK3CA-characterized cohort of 266 HNSCC patients and explored the mechanism in relevant preclinical models including patient-derived xenografts. Among subjects with PIK3CA mutations or amplification, regular NSAID use (≥6 mo) conferred markedly prolonged disease-specific survival (DSS; hazard ratio 0.23, P = 0.0032, 95% CI 0.09-0.62) and overall survival (OS; hazard ratio 0.31, P = 0.0043, 95% CI 0.14-0.69) compared with nonregular NSAID users. For PIK3CA-altered HNSCC, predicted 5-yr DSS was 72% for NSAID users and 25% for nonusers; predicted 5-yr OS was 78% for regular NSAID users and 45% for nonregular users. PIK3CA mutation predicted sensitivity to NSAIDs in preclinical models in association with increased systemic PGE2 production. These findings uncover a biologically plausible rationale to implement NSAID therapy in PIK3CA-altered HNSCC.

4.
J Kidney Cancer VHL ; 5(1): 1-6, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29354391

RESUMO

Sarcomatoid renal cell carcinoma (sRCC) is a highly aggressive form of dedifferentiated renal cell carcinoma. We report a 62-year-old man who presented with respiratory symptoms and a lung mass on chest computed tomography (CT). The patient underwent positron emission tomography/computed tomography (PET/CT) with 18F-fluorodeoxyglucose (18F-FDG) and was found to have extensive metastatic disease. Based on the history and imaging findings, there were possible primary malignancies, including bronchogenic carcinoma, melanoma, or an aggressive lymphoma. An excisional biopsy surprisingly revealed a high-grade sarcomatoid carcinoma with no evidence of differentiation, and immunohistochemical (IHC) studies showed that the tumor cells were positive for markers of genitourinary origin (PAX-8 and vimentin). The histologic and IHC results, along with multiple FDG-avid exophytic lesions in both kidneys, were considered diagnostic of sRCC. Here we have highlighted the potential role of 18F-FDG-PET-CT in patients with sRCC, discussed the diagnostic challenges, and presented a brief review.

5.
J Clin Invest ; 128(1): 207-218, 2018 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-29202462

RESUMO

Synovial sarcoma (SS) is an aggressive soft-tissue sarcoma that is often discovered during adolescence and young adulthood. Despite the name, synovial sarcoma does not typically arise from a synoviocyte but instead arises in close proximity to bones. Previous work demonstrated that mice expressing the characteristic SS18-SSX fusion oncogene in myogenic factor 5-expressing (Myf5-expressing) cells develop fully penetrant sarcomagenesis, suggesting skeletal muscle progenitor cell origin. However, Myf5 is not restricted to committed myoblasts in embryos but is also expressed in multipotent mesenchymal progenitors. Here, we demonstrated that human SS and mouse tumors arising from SS18-SSX expression in the embryonic, but not postnatal, Myf5 lineage share an anatomic location that is frequently adjacent to bone. Additionally, we showed that SS can originate from periosteal cells expressing SS18-SSX alone and from preosteoblasts expressing the fusion oncogene accompanied by the added stabilization of ß-catenin, which is a common secondary change in SS. Expression and secretion of the osteoclastogenesis inhibitory factor osteoprotegerin enabled early growth of SS18-SSX2-transformed cells, indicating a paracrine link between the bone and synovial sarcomagenesis. These findings explain the skeletal contact frequently observed in human SS and may provide alternate means of enabling SS18-SSX-driven oncogenesis in cells as differentiated as preosteoblasts.

6.
Nat Commun ; 8: 14121, 2017 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-28098136

RESUMO

Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders the understanding of NPC biology, disease progression and rational therapy design. Here we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-κB pathway, including CYLD, TRAF3, NFKBIA and NLRC5, in a total of 41% of cases. Functional analysis confirmed inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent membrane protein 1 (LMP1) functions to constitutively activate NF-κB signalling, and we observed mutual exclusivity among tumours with somatic NF-κB pathway aberrations and LMP1-overexpression, suggesting that NF-κB activation is selected for by both somatic and viral events during NPC pathogenesis.


Assuntos
Carcinoma/genética , Infecções por Vírus Epstein-Barr/genética , Exoma , Mutação , NF-kappa B/metabolismo , Neoplasias Nasofaríngeas/genética , Transdução de Sinais , Carcinoma/metabolismo , Carcinoma/fisiopatologia , Proliferação de Células , Enzima Desubiquitinante CYLD/genética , Enzima Desubiquitinante CYLD/metabolismo , Infecções por Vírus Epstein-Barr/metabolismo , Infecções por Vírus Epstein-Barr/fisiopatologia , Infecções por Vírus Epstein-Barr/virologia , Genoma Humano , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/metabolismo , Humanos , Inibidor de NF-kappaB alfa/genética , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/genética , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/fisiopatologia , Fator 3 Associado a Receptor de TNF/genética , Fator 3 Associado a Receptor de TNF/metabolismo , Proteínas da Matriz Viral/genética , Proteínas da Matriz Viral/metabolismo , Sequenciamento Completo do Genoma
7.
Head Neck ; 38(12): 1759-1764, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27232378

RESUMO

BACKGROUND: Patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) demonstrate aberrant activation of the phosphotidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. We examined the efficacy of everolimus, an mTOR inhibitor, in patients with recurrent or metastatic HNSCC. METHODS: This single-arm phase II study enrolled biomarker-unselected patients with recurrent or metastatic HNSCC who failed at least 1 prior therapy. Everolimus was administered until progressive disease or unacceptable toxicity. Primary endpoint was clinical benefit rate (CBR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and evaluation of tissue and serum biomarkers related to the PIK3CA pathway. RESULTS: Seven of 9 patients treated in the first stage were evaluable. No objective responses were seen; CBR was 28%. Three patients discontinued everolimus because of toxicity. Median PFS and OS were 1.5 and 4.5 months, respectively. No activating PI3K mutations were identified in available tumor tissue. CONCLUSION: Everolimus was not active as monotherapy in unselected patients with recurrent/metastatic HNSCC. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1759-1764, 2016.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Everolimo/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/mortalidade , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Everolimo/efeitos adversos , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Medição de Risco , Análise de Sobrevida , Resultado do Tratamento
9.
J Clin Invest ; 126(1): 169-80, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26619122

RESUMO

BACKGROUND: Recurrence and/or metastasis occurs in more than half of patients with head and neck squamous cell carcinoma (HNSCC), and these events pose the greatest threats to long-term survival. We set out to identify genetic alterations that underlie recurrent/metastatic HNSCC. METHODS: Whole-exome sequencing (WES) was performed on genomic DNA extracted from fresh-frozen whole blood and patient-matched tumor pairs from 13 HNSCC patients with synchronous lymph node metastases and 10 patients with metachronous recurrent tumors. Mutational concordance within and between tumor pairs was used to analyze the spatiotemporal evolution of HNSCC in individual patients and to identify potential therapeutic targets for functional evaluation. RESULTS: Approximately 86% and 60% of single somatic nucleotide variants (SSNVs) identified in synchronous nodal metastases and metachronous recurrent tumors, respectively, were transmitted from the primary index tumor. Genes that were mutated in more than one metastatic or recurrent tumor, but not in the respective primary tumors, include C17orf104, inositol 1,4,5-trisphosphate receptor, type 3 (ITPR3), and discoidin domain receptor tyrosine kinase 2 (DDR2). Select DDR2 mutations have been shown to confer enhanced sensitivity to SRC-family kinase (SFK) inhibitors in other malignancies. Similarly, HNSCC cell lines harboring endogenous and engineered DDR2 mutations were more sensitive to the SFK inhibitor dasatinib than those with WT DDR2. CONCLUSION: In this WES study of patient-matched tumor pairs in HNSCC, we found synchronous lymph node metastases to be genetically more similar to their paired index primary tumors than metachronous recurrent tumors. This study outlines a compendium of somatic mutations in primary, metastatic, and/or recurrent HNSCC cancers, with potential implications for precision medicine approaches. FUNDING: National Cancer Institute, American Cancer Society, Agency for Science, Technology and Research of Singapore, and Gilead Sciences Inc.


Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias de Cabeça e Pescoço/genética , Recidiva Local de Neoplasia/genética , Adulto , Idoso , Carcinoma de Células Escamosas/patologia , Dasatinibe/uso terapêutico , Receptores com Domínio Discoidina , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Receptores de Inositol 1,4,5-Trifosfato/genética , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Mutação , Receptores Proteína Tirosina Quinases/genética , Receptores Mitogênicos/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço
10.
J Clin Invest ; 124(9): 3741-56, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25061874

RESUMO

Aberrant activation of EGFR in human cancers promotes tumorigenesis through stimulation of AKT signaling. Here, we determined that the discoidina neuropilin-like membrane protein DCBLD2 is upregulated in clinical specimens of glioblastomas and head and neck cancers (HNCs) and is required for EGFR-stimulated tumorigenesis. In multiple cancer cell lines, EGFR activated phosphorylation of tyrosine 750 (Y750) of DCBLD2, which is located within a recently identified binding motif for TNF receptor-associated factor 6 (TRAF6). Consequently, phosphorylation of DCBLD2 Y750 recruited TRAF6, leading to increased TRAF6 E3 ubiquitin ligase activity and subsequent activation of AKT, thereby enhancing EGFR-driven tumorigenesis. Moreover, evaluation of patient samples of gliomas and HNCs revealed an association among EGFR activation, DCBLD2 phosphorylation, and poor prognoses. Together, our findings uncover a pathway in which DCBLD2 functions as a signal relay for oncogenic EGFR signaling to promote tumorigenesis and suggest DCBLD2 and TRAF6 as potential therapeutic targets for human cancers that are associated with EGFR activation.


Assuntos
Carcinogênese , Receptores ErbB/fisiologia , Proteínas de Membrana/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Fator 6 Associado a Receptor de TNF/metabolismo , Neoplasias Encefálicas/etiologia , Células Cultivadas , Glioma/etiologia , Neoplasias de Cabeça e Pescoço/etiologia , Humanos , Proteínas de Membrana/genética , Fosforilação , Transdução de Sinais
11.
Head Neck ; 36(4): 511-6, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23780921

RESUMO

BACKGROUND: The significance of human papillomavirus (HPV) in nasopharyngeal carcinomas (NPCs) in a low-incidence population remains unknown. METHODS: Samples from 90 patients with NPC (years, 1957-2012) were analyzed for Epstein-Barr virus (EBV). Clinical data, EBV, HPV, and p16 status were correlated with overall survival (OS; 63 cases; years, 1981-2012). RESULTS: Of 9 HPV-positive cases, 3 extended from extra-nasopharyngeal sites. Nasopharyngeal origin was confirmed in 6 cases. HPV-positive NPC had OS similar to EBV-positive NPC (85 vs 141 months; p > .05). The OS of patients with EBV/HPV-negative NPC was worse (34 months; p = .004). Nonkeratinizing histology was associated with better outcome than keratinizing (115 vs 25 months; p = .001). Over the last several decades, the proportion of keratinizing NPC decreased from 34.5% to 14.3% (p = .026). CONCLUSION: The etiologic role of HPV in NPC is confirmed. The favorable prognostic significance of HPV positivity is similar to that of EBV positivity.


Assuntos
Carcinoma/virologia , Herpesvirus Humano 4/isolamento & purificação , Neoplasias Nasofaríngeas/virologia , Papillomaviridae/isolamento & purificação , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/mortalidade , Infecções por Vírus Epstein-Barr/epidemiologia , Feminino , Herpesvirus Humano 4/genética , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Nasofaríngeas/mortalidade , Papillomaviridae/genética , Infecções por Papillomavirus/epidemiologia , Pennsylvania/epidemiologia , Prevalência , Washington/epidemiologia , Adulto Jovem
12.
Cancer Discov ; 3(7): 761-9, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23619167

RESUMO

Genomic findings underscore the heterogeneity of head and neck squamous cell carcinoma (HNSCC). Identification of mutations that predict therapeutic response would be a major advance. We determined the mutationally altered, targetable mitogenic pathways in a large HNSCC cohort. Analysis of whole-exome sequencing data from 151 tumors revealed the phosphoinositide 3-kinase (PI3K) pathway to be the most frequently mutated oncogenic pathway (30.5%). PI3K pathway-mutated HNSCC tumors harbored a significantly higher rate of mutations in known cancer genes. In a subset of human papillomavirus-positive tumors, PIK3CA or PIK3R1 was the only mutated cancer gene. Strikingly, all tumors with concurrent mutation of multiple PI3K pathway genes were advanced (stage IV), implicating concerted PI3K pathway aberrations in HNSCC progression. Patient-derived tumorgrafts with canonical and noncanonical PIK3CA mutations were sensitive to an mTOR/PI3K inhibitor (BEZ-235), in contrast to PIK3CA-wild-type tumorgrafts. These results suggest that PI3K pathway mutations may serve as predictive biomarkers for treatment selection.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Neoplasias de Cabeça e Pescoço/genética , Fosfatidilinositol 3-Quinases/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Neoplasias de Cabeça e Pescoço/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imidazóis/administração & dosagem , Mutação , Estadiamento de Neoplasias , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética , Quinolinas/administração & dosagem , Carcinoma de Células Escamosas de Cabeça e Pescoço
13.
Cancer Res ; 69(8): 3657-64, 2009 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-19351831

RESUMO

Previously, we reported modeling synovial sarcomas in mice by conditionally expressing the human t(X;18) translocation-derived SYT-SSX2 fusion protein in Myf5-expressing myoblasts. Using a tamoxifen-inducible CreER system in mice, we show here that sporadic expression of SYT-SSX2 across multiple tissue types leads to exclusive formation of synovial sarcoma-like tumors, whereas its widespread expression is lethal. Certain clinical and histologic features of tumors in this new model suggest additional nonmyoblast origin for synovial sarcoma. CreER-based sporadic expression both avoids the severe early developmental phenotypes associated with widespread SYT-SSX2 expression and better models natural pathogenesis of cancers in which transformed cells usually arise within an environment of largely normal cells. Furthermore, this strategy may recapitulate multiple potential cellular origins within a single model system.


Assuntos
Integrases/genética , Sarcoma Sinovial/genética , Sarcoma Sinovial/patologia , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Animais , Camundongos , Proteínas de Fusão Oncogênica/biossíntese , Proteínas de Fusão Oncogênica/genética , Translocação Genética
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