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1.
Breast Cancer Res Treat ; 186(2): 391-401, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33576900

RESUMO

PURPOSE: Triple-negative breast cancer (TNBC) is an aggressive subtype most prevalent among women of Western Sub-Saharan African ancestry. It accounts for 15-25% of African American (AA) breast cancers (BC) and up to 80% of Ghanaian breast cancers, thus contributing to outcome disparities in BC for black women. The aggressive biology of TNBC has been shown to be regulated partially by breast cancer stem cells (BCSC) which mediate tumor recurrence and metastasis and are more abundant in African breast tumors. METHODS: We studied the biological differences between TNBC in women with African ancestry and those of Caucasian women by comparing the gene expression of the BCSC. From low-passage patient derived xenografts (PDX) from Ghanaian (GH), AA, and Caucasian American (CA) TNBCs, we sorted for and sequenced the stem cell populations and analyzed for differential gene enrichment. RESULTS: In our cohort of TNBC tumors, we observed that the ALDH expressing stem cells display distinct ethnic specific gene expression patterns, with the largest difference existing between the GH and AA ALDH+ cells. Furthermore, the tumors from the women of African ancestry [GH/AA] had ALDH stem cell (SC) enrichment for expression of immune related genes and processes. Among the significantly upregulated genes were CD274 (PD-L1), CXCR9, CXCR10 and IFI27, which could serve as potential drug targets. CONCLUSIONS: Further exploration of the role of immune regulated genes and biological processes in BCSC may offer insight into developing novel approaches to treating TNBC to help ameliorate survival disparities in women with African ancestry.


Assuntos
Neoplasias de Mama Triplo Negativas , Negro ou Afro-Americano/genética , Feminino , Gana/epidemiologia , Humanos , Recidiva Local de Neoplasia , Neoplasias de Mama Triplo Negativas/genética , População Branca
2.
Nature ; 471(7339): 467-72, 2011 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-21430775

RESUMO

Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumour genomes and their comparison to matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the data set. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-κB signalling was indicated by mutations in 11 members of the NF-κB pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge.


Assuntos
Genoma Humano/genética , Mieloma Múltiplo/genética , Mutação/genética , Sequência de Aminoácidos , Coagulação Sanguínea/genética , Ilhas de CpG/genética , Análise Mutacional de DNA , Reparo do DNA/genética , Éxons/genética , Complexo Multienzimático de Ribonucleases do Exossomo , Genômica , Histonas/metabolismo , Proteínas de Homeodomínio/genética , Homeostase/genética , Humanos , Metilação , Modelos Moleculares , Dados de Sequência Molecular , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/enzimologia , Mieloma Múltiplo/metabolismo , NF-kappa B/metabolismo , Oncogenes/genética , Fases de Leitura Aberta/genética , Biossíntese de Proteínas/genética , Conformação Proteica , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Processamento Pós-Transcricional do RNA/genética , Ribonucleases/química , Ribonucleases/genética , Transdução de Sinais/genética , Transcrição Gênica/genética
3.
Cancer Cell ; 12(2): 131-44, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17692805

RESUMO

Activation of NF-kappaB has been noted in many tumor types, however only rarely has this been linked to an underlying genetic mutation. An integrated analysis of high-density oligonucleotide array CGH and gene expression profiling data from 155 multiple myeloma samples identified a promiscuous array of abnormalities contributing to the dysregulation of NF-kappaB in approximately 20% of patients. We report mutations in ten genes causing the inactivation of TRAF2, TRAF3, CYLD, cIAP1/cIAP2 and activation of NFKB1, NFKB2, CD40, LTBR, TACI, and NIK that result primarily in constitutive activation of the noncanonical NF-kappaB pathway, with the single most common abnormality being inactivation of TRAF3. These results highlight the critical importance of the NF-kappaB pathway in the pathogenesis of multiple myeloma.


Assuntos
Regulação Neoplásica da Expressão Gênica , Mieloma Múltiplo/genética , Mutação/genética , NF-kappa B/genética , Proteínas de Neoplasias/metabolismo , Adenoviridae , Proteína 3 com Repetições IAP de Baculovírus , Antígenos CD40/genética , Antígenos CD40/metabolismo , Células Cultivadas , Enzima Desubiquitinante CYLD , Ativação Enzimática , Imunofluorescência , Deleção de Genes , Perfilação da Expressão Gênica , Humanos , Immunoblotting , Técnicas Imunoenzimáticas , Hibridização in Situ Fluorescente , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Receptor beta de Linfotoxina/genética , Receptor beta de Linfotoxina/metabolismo , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , NF-kappa B/metabolismo , Subunidade p50 de NF-kappa B/genética , Subunidade p50 de NF-kappa B/metabolismo , Subunidade p52 de NF-kappa B/genética , Subunidade p52 de NF-kappa B/metabolismo , Proteínas de Neoplasias/genética , Hibridização de Ácido Nucleico , Plasmídeos , Reação em Cadeia da Polimerase , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Fator 2 Associado a Receptor de TNF/genética , Fator 2 Associado a Receptor de TNF/metabolismo , Fator 3 Associado a Receptor de TNF/genética , Fator 3 Associado a Receptor de TNF/metabolismo , Transfecção , Proteína Transmembrana Ativadora e Interagente do CAML/genética , Proteína Transmembrana Ativadora e Interagente do CAML/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases , Quinase Induzida por NF-kappaB
4.
Nat Med ; 28(4): 704-712, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35228755

RESUMO

Previous studies have suggested that the gut microbiome influences the response to checkpoint inhibitors (CPIs) in patients with cancer. CBM588 is a bifidogenic live bacterial product that we postulated could augment CPI response through modulation of the gut microbiome. In this open-label, single-center study (NCT03829111), 30 treatment-naive patients with metastatic renal cell carcinoma with clear cell and/or sarcomatoid histology and intermediate- or poor-risk disease were randomized 2:1 to receive nivolumab and ipilimumab with or without daily oral CBM588, respectively. Stool metagenomic sequencing was performed at multiple timepoints. The primary endpoint to compare the relative abundance of Bifidobacterium spp. at baseline and at 12 weeks was not met, and no significant differences in Bifidobacterium spp. or Shannon index associated with the addition of CBM588 to nivolumab-ipilimumab were detected. Secondary endpoints included response rate, progression-free survival (PFS) and toxicity. PFS was significantly longer in patients receiving nivolumab-ipilimumab with CBM588 than without (12.7 months versus 2.5 months, hazard ratio 0.15, 95% confidence interval 0.05-0.47, P = 0.001). Although not statistically significant, the response rate was also higher in patients receiving CBM588 (58% versus 20%, P = 0.06). No significant difference in toxicity was observed between the study arms. The data suggest that CBM588 appears to enhance the clinical outcome in patients with metastatic renal cell carcinoma treated with nivolumab-ipilimumab. Larger studies are warranted to confirm this clinical observation and elucidate the mechanism of action and the effects on microbiome and immune compartments.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células Renais , Neoplasias Renais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Suplementos Nutricionais , Feminino , Humanos , Ipilimumab/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Masculino , Nivolumabe/uso terapêutico
5.
PLoS Med ; 5(1): e8, 2008 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-18215105

RESUMO

BACKGROUND: There is much discussion in the cancer drug development community about how to incorporate molecular tools into early-stage clinical trials to assess target modulation, measure anti-tumor activity, and enrich the clinical trial population for patients who are more likely to benefit. Small, molecularly focused clinical studies offer the promise of the early definition of optimal biologic dose and patient population. METHODS AND FINDINGS: Based on preclinical evidence that phosphatase and tensin homolog deleted on Chromosome 10 (PTEN) loss sensitizes tumors to the inhibition of mammalian target of rapamycin (mTOR), we conducted a proof-of-concept Phase I neoadjuvant trial of rapamycin in patients with recurrent glioblastoma, whose tumors lacked expression of the tumor suppressor PTEN. We aimed to assess the safety profile of daily rapamycin in patients with glioma, define the dose of rapamycin required for mTOR inhibition in tumor tissue, and evaluate the antiproliferative activity of rapamycin in PTEN-deficient glioblastoma. Although intratumoral rapamycin concentrations that were sufficient to inhibit mTOR in vitro were achieved in all patients, the magnitude of mTOR inhibition in tumor cells (measured by reduced ribosomal S6 protein phosphorylation) varied substantially. Tumor cell proliferation (measured by Ki-67 staining) was dramatically reduced in seven of 14 patients after 1 wk of rapamycin treatment and was associated with the magnitude of mTOR inhibition (p = 0.0047, Fisher exact test) but not the intratumoral rapamycin concentration. Tumor cells harvested from the Ki-67 nonresponders retained sensitivity to rapamycin ex vivo, indicating that clinical resistance to biochemical mTOR inhibition was not cell-intrinsic. Rapamycin treatment led to Akt activation in seven patients, presumably due to loss of negative feedback, and this activation was associated with shorter time-to-progression during post-surgical maintenance rapamycin therapy (p < 0.05, Logrank test). CONCLUSIONS: Rapamycin has anticancer activity in PTEN-deficient glioblastoma and warrants further clinical study alone or in combination with PI3K pathway inhibitors. The short-term treatment endpoints used in this neoadjuvant trial design identified the importance of monitoring target inhibition and negative feedback to guide future clinical development. TRIAL REGISTRATION: http://www.ClinicalTrials.gov (#NCT00047073).


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Proteínas de Neoplasias/antagonistas & inibidores , PTEN Fosfo-Hidrolase/deficiência , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Quinases/fisiologia , Terapia de Salvação , Sirolimo/uso terapêutico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/cirurgia , Divisão Celular/efeitos dos fármacos , Terapia Combinada , Progressão da Doença , Retroalimentação Fisiológica , Feminino , Glioblastoma/enzimologia , Glioblastoma/genética , Glioblastoma/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/cirurgia , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/fisiologia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína S6 Ribossômica/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirolimo/efeitos adversos , Sirolimo/farmacologia , Serina-Treonina Quinases TOR
6.
Eur J Hum Genet ; 15(1): 94-102, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17063143

RESUMO

High numbers of melanocytic naevi (moles), and mutations in the p16 gene (CDKN2A), are two strong risk factors for cutaneous malignant melanoma. We have previously reported linkage of mole count to the CDKN2A locus. Here, we report genome-wide scans for mole counts (differentiated into flat, raised and atypical subtypes) with a total of 796 microsatellite markers for 424 families with 1024 twins and siblings, plus genotypes for 690 parents. Inclusion of 221 pairs of MZ twins enabled separation of shared environmental and polygenic influences, so placing an upper limit to estimates of QTL variance. Maximum likelihood multipoint variance component methods were used to assess linkage of naevus count. Sex, age, body surface area, skin colour, hair colour, sunburn and facial freckles were included as covariates. Peak linkage of flat mole count was to regions on chromosomes 2, 9, 8 and 17 with lod scores 2.95, 2.95, 2.50 and 2.15, respectively. The support for linkage to the CDKN2A gene region (9p21) increased to 3.42 when additional fine mapping markers were added. For raised mole count, there was suggestive evidence of linkage in our sample to chromosome 16 (lod=1.87), and for atypical mole count on chromosomes 1, 6 and X with lod scores of 2.20, 2.00 and 2.00, respectively. The multivariate linkage peaks generally match those from individual trait analyses, with the exception of a new peak on chromosome 4 (point-wise empirical P-value=0.001). We replicate our earlier finding of linkage to CDKN2A and discovering linkage to several novel regions that may also influence risk of the development of malignant melanoma.


Assuntos
Genes p16 , Nevo Pigmentado/genética , Adolescente , Austrália , Feminino , Genoma Humano , Humanos , Escore Lod , Masculino , Melanoma/epidemiologia , Herança Multifatorial , Análise Multivariada , Nevo Pigmentado/epidemiologia , Nevo Pigmentado/patologia , Fatores de Risco
7.
Cancer Cell ; 28(4): 500-514, 2015 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-26461094

RESUMO

Plasmodium falciparum engineer infected erythrocytes to present the malarial protein, VAR2CSA, which binds a distinct type chondroitin sulfate (CS) exclusively expressed in the placenta. Here, we show that the same CS modification is present on a high proportion of malignant cells and that it can be specifically targeted by recombinant VAR2CSA (rVAR2). In tumors, placental-like CS chains are linked to a limited repertoire of cancer-associated proteoglycans including CD44 and CSPG4. The rVAR2 protein localizes to tumors in vivo and rVAR2 fused to diphtheria toxin or conjugated to hemiasterlin compounds strongly inhibits in vivo tumor cell growth and metastasis. Our data demonstrate how an evolutionarily refined parasite-derived protein can be exploited to target a common, but complex, malignancy-associated glycosaminoglycan modification.


Assuntos
Antígenos de Protozoários/genética , Sulfatos de Condroitina/metabolismo , Melanoma Experimental/terapia , Placenta/metabolismo , Proteínas Recombinantes/administração & dosagem , Neoplasias Cutâneas/terapia , Animais , Antígenos de Protozoários/metabolismo , Linhagem Celular Tumoral , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Feminino , Células HEK293 , Células Endoteliais da Veia Umbilical Humana , Humanos , Receptores de Hialuronatos/metabolismo , Melanoma Experimental/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Terapia de Alvo Molecular , Oligopeptídeos/genética , Oligopeptídeos/metabolismo , Especificidade de Órgãos , Gravidez , Proteínas Recombinantes/farmacologia , Neoplasias Cutâneas/metabolismo
8.
Cancer Causes Control ; 17(3): 229-37, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16489530

RESUMO

OBJECTIVE: To provide the voice of experience to investigators contemplating engagement in the realm of "team science". METHODS: Leaders were brought together from academia, government, and industry to share perspectives and insights based on real-life experiences. A panel discussion was held at the 2005 annual meeting of the American Association of Cancer Research. This article summarizes that forum. RESULTS: The panel focused on eight specific topics that were determined in advance to be the most important: the main justification for team science, funding team science, pre-arranged versus assigned partnerships, the role of novel technology with industrial partners, recognition for efforts and contribution in team science, budgets, keys to success when bridging disciplines and cultures, and balancing goals between academia and business. Although there were some differences of opinion, there were also a number of areas of agreement. Many practical suggestions were provided on how to succeed in the age of team science. PRINCIPAL CONCLUSION: The nature of scientific discovery in cancer research is increasingly requiring team science. Understanding the perspectives of academia, government, and business in this new world order is essential to successful navigation and, ultimately, major accomplishment in the effort to defeat the disease.


Assuntos
Comportamento Cooperativo , Comunicação Interdisciplinar , Neoplasias/epidemiologia , Pesquisa , Biotecnologia , Orçamentos , Comparação Transcultural , Objetivos , Processos Grupais , Humanos , Neoplasias/economia
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