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Future Virol ; 13(7): 475-482, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30245733


Aim: The goal of this study was to determine if a single AAV vector, encoding Cas9 and guide RNAs specific for the HPV16 E6 and E7 genes, could inhibit the growth of an HPV16-induced tumor in vivo. Materials & methods: We grew HPV16+, patient-derived anal cancer explants in immunodeficient mice and then challenged these by injection of AAV-based vectors encoding Cas9 and control or HPV16-specific guide RNAs. Results & conclusion: We observed a significant and selective reduction in tumor growth when the HPV16 E6 and E7 genes were targeted using Cas9. These studies provide proof of principle for the hypothesis that CRISPR/Cas has the potential to be used to selectively treat HPV-induced tumors in humans.

BJU Int ; 2018 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-29802810


OBJECTIVES: To report the baseline results of a longitudinal psychosocial study that forms part of the IMPACT study, a multi-national investigation of targeted prostate cancer (PCa) screening among men with a known pathogenic germline mutation in the BRCA1 or BRCA2 genes. PARTICPANTS AND METHODS: Men enrolled in the IMPACT study were invited to complete a questionnaire at collaborating sites prior to each annual screening visit. The questionnaire included sociodemographic characteristics and the following measures: the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), 36-item short-form health survey (SF-36), Memorial Anxiety Scale for Prostate Cancer, Cancer Worry Scale-Revised, risk perception and knowledge. The results of the baseline questionnaire are presented. RESULTS: A total of 432 men completed questionnaires: 98 and 160 had mutations in BRCA1 and BRCA2 genes, respectively, and 174 were controls (familial mutation negative). Participants' perception of PCa risk was influenced by genetic status. Knowledge levels were high and unrelated to genetic status. Mean scores for the HADS and SF-36 were within reported general population norms and mean IES scores were within normal range. IES mean intrusion and avoidance scores were significantly higher in BRCA1/BRCA2 carriers than in controls and were higher in men with increased PCa risk perception. At the multivariate level, risk perception contributed more significantly to variance in IES scores than genetic status. CONCLUSION: This is the first study to report the psychosocial profile of men with BRCA1/BRCA2 mutations undergoing PCa screening. No clinically concerning levels of general or cancer-specific distress or poor quality of life were detected in the cohort as a whole. A small subset of participants reported higher levels of distress, suggesting the need for healthcare professionals offering PCa screening to identify these risk factors and offer additional information and support to men seeking PCa screening.

Br J Cancer ; 118(2): 266-276, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29301143


BACKGROUND: Prostate-specific antigen (PSA) and PSA-velocity (PSAV) have been used to identify men at risk of prostate cancer (PrCa). The IMPACT study is evaluating PSA screening in men with a known genetic predisposition to PrCa due to BRCA1/2 mutations. This analysis evaluates the utility of PSA and PSAV for identifying PrCa and high-grade disease in this cohort. METHODS: PSAV was calculated using logistic regression to determine if PSA or PSAV predicted the result of prostate biopsy (PB) in men with elevated PSA values. Cox regression was used to determine whether PSA or PSAV predicted PSA elevation in men with low PSAs. Interaction terms were included in the models to determine whether BRCA status influenced the predictiveness of PSA or PSAV. RESULTS: 1634 participants had ⩾3 PSA readings of whom 174 underwent PB and 45 PrCas diagnosed. In men with PSA >3.0 ng ml-l, PSAV was not significantly associated with presence of cancer or high-grade disease. PSAV did not add to PSA for predicting time to an elevated PSA. When comparing BRCA1/2 carriers to non-carriers, we found a significant interaction between BRCA status and last PSA before biopsy (P=0.031) and BRCA2 status and PSAV (P=0.024). However, PSAV was not predictive of biopsy outcome in BRCA2 carriers. CONCLUSIONS: PSA is more strongly predictive of PrCa in BRCA carriers than non-carriers. We did not find evidence that PSAV aids decision-making for BRCA carriers over absolute PSA value alone.

PLoS One ; 12(1): e0169439, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28060954


BACKGROUND: Standard of care treatment for colorectal cancer liver metastasis consists of a cytotoxic chemotherapy in combination with a targeted agent. Clinical trials have guided the use of these combinatory therapies, but it remains unclear what the optimal combinations of cytotoxic chemotherapy with a targeted agent are. METHODS: Using a genomic based approach, gene expression profiling was obtained from tumor samples of patient with colorectal cancer liver metastasis who received an oxaliplatin based therapy. Early passaged colorectal cancer liver metastasis cell lines and patient derived xenografts of colorectal cancer liver metastasis were then treated with oxaliplatin and a mTOR inhibitor. RESULTS: Gene set enrichment analysis revealed that the mTOR pathway was activated in patients receiving oxaliplatin based therapy. Treatment of early passaged colorectal cancer lines and patient derived xenografts with oxaliplatin resulted in activation of the mTOR pathway. Combination therapy with oxaliplatin and a mTOR inhibitor resulted in a synergistic effect both in vitro and in vivo. CONCLUSION: Our findings suggest a genomic based approach can be used to identify optimal combinations of cytotoxic chemotherapy with a targeted agent and that these observations can be validated both in vitro and in vivo using patient derived colorectal cancer cell lines and patient derived xenografts prior to clinical use.

Antineoplásicos/farmacologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/metabolismo , Compostos Organoplatínicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Análise por Conglomerados , Neoplasias Colorretais/terapia , Terapia Combinada , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Concentração Inibidora 50 , Neoplasias Hepáticas/terapia , Masculino , Camundongos , Oxaliplatina , Transcriptoma , Ensaios Antitumorais Modelo de Xenoenxerto
Cancer Res ; 69(19): 7803-10, 2009 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-19773438


Loss of PTEN and activation of phosphoinositide 3-kinase are commonly observed in advanced prostate cancer. Inhibition of mammalian target of rapamycin (mTOR), a downstream target of phosphoinositide 3-kinase signaling, results in cell cycle arrest and apoptosis in multiple in vitro and in vivo models of prostate cancer. However, single-agent use of mTOR inhibition has limited clinical success, and the identification of molecular events mitigating tumor response to mTOR inhibition remains a critical question. Here, using genetically engineered human prostate epithelial cells (PrEC), we show that MYC, a frequent target of genetic gain in prostate cancers, abrogates sensitivity to rapamycin by decreasing rapamycin-induced cytostasis and autophagy. Analysis of MYC and the mTOR pathway in human prostate tumors and PrEC showed selective increased expression of eukaryotic initiation factor 4E-binding protein 1 (4EBP1) with gain in MYC copy number or forced MYC expression, respectively. We have also found that MYC binds to regulatory regions of the 4EBP1 gene. Suppression of 4EBP1 expression resulted in resensitization of MYC-expressing PrEC to rapamycin and increased autophagy. Taken together, our findings suggest that MYC expression abrogates sensitivity to rapamycin through increased expression of 4EBP1 and reduced autophagy.

Antibióticos Antineoplásicos/farmacologia , Fator de Iniciação 4E em Eucariotos/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Proteínas Proto-Oncogênicas c-myc/metabolismo , Sirolimo/farmacologia , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Elementos E-Box , Fator de Iniciação 4E em Eucariotos/biossíntese , Fator de Iniciação 4E em Eucariotos/genética , Genes myc , Humanos , Masculino , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Quinases/biossíntese , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-myc/biossíntese , Proteínas Proto-Oncogênicas c-myc/genética , Serina-Treonina Quinases TOR , Tunicamicina/farmacologia