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1.
Nat Commun ; 12(1): 808, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33547292

RESUMO

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings build on prior work and shed light on the molecular drivers of aggressivity and responsiveness to ICI of S/R RCC.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Renais/imunologia , Regulação Neoplásica da Expressão Gênica , /imunologia , Neoplasias Renais/imunologia , Tumor Rabdoide/imunologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/mortalidade , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/imunologia , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/mortalidade , Mutação , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/imunologia , Estudos Retrospectivos , Tumor Rabdoide/tratamento farmacológico , Tumor Rabdoide/genética , Tumor Rabdoide/mortalidade , Transdução de Sinais , Análise de Sobrevida , Transcrição Genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/imunologia , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/imunologia
2.
Mol Cancer Res ; 2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33168599

RESUMO

Gleason score, a measure of prostate tumor differentiation, is the strongest predictor of lethal prostate cancer at the time of diagnosis. Metabolomic profiling of tumor and of patient serum could identify biomarkers of aggressive disease and lead to the development of a less-invasive assay to perform active surveillance monitoring. Metabolomic profiling of prostate tissue and serum samples was performed. Metabolite levels and metabolite-set were compared pathways across Gleason scores. Machine learning algorithms were trained and tuned to predict transformation or differentiation status from metabolite data. 135 metabolites were significantly different (adjusted p<0.05) in tumor vs normal tissue, and pathway analysis identified one sugar metabolism pathway (adjusted p=0.03). Machine learning identified profiles that predicted tumor versus normal tissue (AUC of 0.82 ± 0.08). In tumor tissue, 25 metabolites were associated with Gleason score (unadjusted p<0.05), 4 increased in high grade while the remainder were enriched in low grade. While pyroglutamine and 1,5-anhydroglucitol were correlated (0.73 and 0.72, respectively) between tissue and serum from the same patient, no metabolites were consistently associated with Gleason score in serum. Previously reported as well as novel metabolites with differing abundance were identified across tumor tissue. However, a "metabolite signature" for Gleason score was not obtained. This may be due to study design and analytical challenges that future studies should consider. Implications: Metabolic profiling can distinguish benign and neoplastic tissues. A novel unsupervised machine learning method can be utilized to achieve this distinction.

4.
Clin Cancer Res ; 26(23): 6122-6131, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32943461

RESUMO

PURPOSE: Androgen receptor (AR) inhibition can upregulate c-MET expression, which may be a resistance mechanism driving progression of castration-resistant prostate cancer (CRPC). We conducted a phase I trial investigating the safety and pharmacokinetics of a potent c-MET inhibitor, crizotinib, with the AR antagonist, enzalutamide, in CRPC. PATIENTS AND METHODS: Employing a 3+3 dose-escalation design, we tested three dose levels of crizotinib (250 mg daily, 200 mg twice a day, and 250 mg twice a day) with standard-dose enzalutamide (160 mg daily). The primary endpoint was rate of dose-limiting toxicities (DLTs). Tolerability and pharmacokinetics profile were secondary endpoints. RESULTS: Twenty-four patients were enrolled in the dose-escalation (n = 16) and dose-expansion (n = 8) phases. Two DLTs occurred in dose escalation (grade 3 alanine aminotransferase elevation). The MTD of crizotinib was 250 mg twice a day. Most frequent treatment-related adverse events were fatigue (50%), transaminitis (38%), nausea (33%), and vomiting, constipation, and diarrhea (21% each). Grade ≥3 events (25%) included transaminitis (n = 2), fatigue (n = 1), hypertension (n = 1), pulmonary embolism (n = 1), and a cardiac event encompassing QTc prolongation/ventricular arrhythmia/cardiac arrest. Median progression-free survival was 5.5 months (95% confidence interval, 2.8-21.2). Pharmacokinetics analysis at the MTD (n = 12) revealed a mean C max ss of 104 ± 45 ng/mL and AUCτ ss of 1,000 ± 476 ng•h/mL, representing a 74% decrease in crizotinib systemic exposure relative to historical data (C max ss, 315 ng/mL and AUCτ ss, 3,817 ng•h/mL). CONCLUSIONS: Concurrent administration of enzalutamide and crizotinib resulted in a clinically significant 74% decrease in systemic crizotinib exposure. Further investigation of this combination in CRPC is not planned. Our results highlight the importance of evaluating pharmacokinetics interactions when evaluating novel combination strategies in CRPC.

5.
J Natl Cancer Inst ; 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32853339

RESUMO

BACKGROUND: There is an urgent need to identify factors specifically associated with aggressive prostate cancer (PCa) risk. We investigated whether rare pathogenic, likely pathogenic, or deleterious (P/LP/D) germline variants in DNA repair genes are associated with aggressive PCa risk in a case-case study of aggressive versus non-aggressive disease. METHODS: Participants were 5,545 European-ancestry men, including 2,775 non-aggressive and 2,770 aggressive PCa cases, which included 467 metastatic cases (16.9%). Samples were assembled from 12 international studies and germline sequenced together. Rare (minor allele frequency<0.01) P/LP/D variants were analyzed for 155 DNA repair genes. We compared single variant, gene-based, and DNA repair pathway-based burdens by disease aggressiveness. All statistical tests are two-sided. RESULTS: BRCA2 and PALB2 had the most statistically significant gene-based associations, with 2.5% of aggressive and 0.8% of non-aggressive cases carrying P/LP/D BRCA2 alleles (OR = 3.19, 95% CI = 1.94 to 5.25, P = 8.58x10-7) and 0.65% of aggressive and 0.11% of non-aggressive cases carrying P/LP/D PALB2 alleles (OR = 6.31, 95% CI = 1.83 to 21.68, P = 4.79x10-4). ATM had a nominal association, with 1.6% of aggressive and 0.8% of non-aggressive cases carrying P/LP/D ATM alleles (OR = 1.88, 95% CI = 1.10 to 3.22, P=.02). In aggregate, P/LP/D alleles within 24 literature-curated candidate PCa DNA repair genes were more common in aggressive than non-aggressive cases (carrier frequencies=14.2% versus 10.6%, respectively; P = 5.56x10-5). However, this difference was statistically non-significant (P=.18) upon excluding BRCA2, PALB2, and ATM. Among these 24 genes, P/LP/D carriers had a 1.06-year younger diagnosis age (95% CI=-1,65 to 0.48, P = 3.71x10-4). CONCLUSIONS: Risk conveyed by DNA repair genes is largely driven by rare P/LP/D alleles within BRCA2, PALB2, and ATM. These findings support the importance of these genes in both screening and disease management considerations.

6.
Nat Genet ; 52(8): 790-799, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32690948

RESUMO

Epigenetic processes govern prostate cancer (PCa) biology, as evidenced by the dependency of PCa cells on the androgen receptor (AR), a prostate master transcription factor. We generated 268 epigenomic datasets spanning two state transitions-from normal prostate epithelium to localized PCa to metastases-in specimens derived from human tissue. We discovered that reprogrammed AR sites in metastatic PCa are not created de novo; rather, they are prepopulated by the transcription factors FOXA1 and HOXB13 in normal prostate epithelium. Reprogrammed regulatory elements commissioned in metastatic disease hijack latent developmental programs, accessing sites that are implicated in prostate organogenesis. Analysis of reactivated regulatory elements enabled the identification and functional validation of previously unknown metastasis-specific enhancers at HOXB13, FOXA1 and NKX3-1. Finally, we observed that prostate lineage-specific regulatory elements were strongly associated with PCa risk heritability and somatic mutation density. Examining prostate biology through an epigenomic lens is fundamental for understanding the mechanisms underlying tumor progression.


Assuntos
Neoplasias da Próstata/genética , Linhagem Celular , Linhagem Celular Tumoral , Progressão da Doença , Epigenômica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Células HEK293 , Fator 3-alfa Nuclear de Hepatócito/genética , Humanos , Masculino , Próstata/patologia , Neoplasias da Próstata/patologia , Receptores Androgênicos/genética , Sequências Reguladoras de Ácido Nucleico/genética
7.
Nat Med ; 26(7): 1041-1043, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32572266

RESUMO

Improving early cancer detection has the potential to substantially reduce cancer-related mortality. Cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) is a highly sensitive assay capable of detecting early-stage tumors. We report accurate classification of patients across all stages of renal cell carcinoma (RCC) in plasma (area under the receiver operating characteristic (AUROC) curve of 0.99) and demonstrate the validity of this assay to identify patients with RCC using urine cell-free DNA (cfDNA; AUROC of 0.86).


Assuntos
Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/genética , Metilação de DNA/genética , Detecção Precoce de Câncer , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/urina , Ácidos Nucleicos Livres/sangue , Ácidos Nucleicos Livres/genética , Ácidos Nucleicos Livres/urina , Epigenoma/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos
9.
Clin Cancer Res ; 26(11): 2673-2680, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32071115

RESUMO

PURPOSE: Prostate cancers with mutations in genes involved in homologous recombination (HR), most commonly BRCA2, respond favorably to PARP inhibition and platinum-based chemotherapy. We investigated whether other prostate tumors that do not harbor deleterious mutations in these particular genes can similarly be deficient in HR, likely rendering those sensitive to HR-directed therapies. EXPERIMENTAL DESIGN: Homologous recombination deficiency (HRD) levels can be estimated using various mutational signatures derived from next-generation sequencing data. We used this approach on whole-genome sequencing (WGS; n = 311) and whole-exome sequencing (WES) data (n = 498) of both primary and metastatic prostate adenocarcinomas to determine whether prostate cancer cases display clear signs of HRD in somatic tumor biopsies. RESULTS: Known BRCA-deficient samples showed all previously described HRD-associated mutational signatures in the WGS data. HRD-associated mutational signatures were also detected in a subset of patients who did not harbor germline or somatic mutations in BRCA1/2 or other HR-related genes. Similar results, albeit with lower sensitivity and accuracy, were also obtained from WES data. CONCLUSIONS: These findings may expand the number of cases likely to respond to PARP inhibitor treatment. On the basis of the HR-associated mutational signatures, 5% to 8% of localized prostate cancer cases may be good candidates for PARP-inhibitor treatment (including those with BRCA1/2 mutations).

10.
Am J Hum Genet ; 106(2): 170-187, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32004450

RESUMO

Although quantitative trait locus (QTL) associations have been identified for many molecular traits such as gene expression, it remains challenging to distinguish the causal nucleotide from nearby variants. In addition to traditional QTLs by association, allele-specific (AS) QTLs are a powerful measure of cis-regulation that are concordant with traditional QTLs but typically less susceptible to technical/environmental noise. However, existing methods for estimating causal variant probabilities (i.e., fine mapping) cannot produce valid estimates from asQTL signals due to complexities in linkage disequilibrium (LD). We introduce PLASMA (Population Allele-Specific Mapping), a fine-mapping method that integrates QTL and asQTL information to improve accuracy. In simulations, PLASMA accurately prioritizes causal variants over a wide range of genetic architectures. Applied to RNA-seq data from 524 kidney tumor samples, PLASMA achieves a greater power at 50 samples than conventional QTL-based fine mapping at 500 samples, with more than 17% of loci fine mapped to within five causal variants, compared to 2% by QTL-based fine mapping, and a 6.9-fold overall reduction in median credible set size compared to QTL-based fine mapping when applied to H3K27AC ChIP-seq from just 28 prostate tumor/normal samples. Variants in the PLASMA credible sets for RNA-seq and ChIP-seq were enriched for open chromatin and chromatin looping, respectively, at a comparable or greater degree than credible variants from existing methods while containing far fewer markers. Our results demonstrate how integrating AS activity can substantially improve the detection of causal variants from existing molecular data.


Assuntos
Algoritmos , Desequilíbrio Alélico , Biomarcadores Tumorais/genética , Mapeamento Cromossômico/métodos , Neoplasias Renais/genética , Neoplasias da Próstata/genética , Locos de Características Quantitativas , Simulação por Computador , Interpretação Estatística de Dados , Humanos , Neoplasias Renais/patologia , Desequilíbrio de Ligação , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/patologia
11.
Eur Urol ; 77(1): 3-10, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30992160

RESUMO

BACKGROUND: The role of elective whole-pelvis radiotherapy (WPRT) remains controversial. Few studies have investigated it in Gleason grade group (GG) 5 prostate cancer (PCa), known to have a high risk of nodal metastases. OBJECTIVE: To assess the impact of WPRT on patients with GG 5 PCa treated with external-beam radiotherapy (EBRT) or EBRT with a brachytherapy boost (EBRT+BT). DESIGN, SETTING, AND PARTICIPANTS: We identified 1170 patients with biopsy-proven GG 5 PCa from 11 centers in the United States and one in Norway treated between 2000 and 2013 (734 with EBRT and 436 with EBRT+BT). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Biochemical recurrence-free survival (bRFS), distant metastasis-free survival (DMFS), and prostate cancer-specific survival (PCSS) were compared using Cox proportional hazards models with propensity score adjustment. RESULTS AND LIMITATIONS: A total of 299 EBRT patients (41%) and 320 EBRT+BT patients (73%) received WPRT. The adjusted 5-yr bRFS rates with WPRT in the EBRT and EBRT+BT groups were 66% and 88%, respectively. Without WPRT, these rates for the EBRT and EBRT+BT groups were 58% and 78%, respectively. The median follow-up was 5.6yr. WPRT was associated with improved bRFS among patients treated with EBRT+BT (hazard ratio [HR] 0.5, 95% confidence interval [CI] 0.2-0.9, p=0.02), but no evidence for improvement was found in those treated with EBRT (HR 0.8, 95% CI 0.6-1.2, p=0.4). WPRT was not significantly associated with improved DMFS or PCSS in the EBRT group (HR 1.1, 95% CI 0.7-1.7, p=0.8 for DMFS and HR 0.7, 95% CI 0.4-1.1, p=0.1 for PCSS), or in the EBRT+BT group (HR 0.6, 95% CI 0.3-1.4, p=0.2 for DMFS and HR 0.5 95% CI 0.2-1.2, p=0.1 for PCSS). CONCLUSIONS: WPRT was not associated with improved PCSS or DMFS in patients with GG 5 PCa who received either EBRT or EBRT+BT. However, WPRT was associated with a significant improvement in bRFS among patients receiving EBRT+BT. Strategies to optimize WPRT, potentially with the use of advanced imaging techniques to identify occult nodal disease, are warranted. PATIENT SUMMARY: When men with a high Gleason grade prostate cancer receive radiation with external radiation and brachytherapy, the addition of radiation to the pelvis results in a longer duration of prostate-specific antigen control. However, we did not find a difference in their survival from prostate cancer or in their survival without metastatic disease. We also did not find a benefit for radiation to the pelvis in men who received radiation without brachytherapy.

12.
Br J Cancer ; 122(4): 555-563, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31857723

RESUMO

BACKGROUND: In metastatic urothelial carcinoma (mUC), predictive biomarkers that correlate with response to immune checkpoint inhibitors (ICIs) are lacking. Here, we interrogated genomic and clinical features associated with response to ICIs in mUC. METHODS: Sixty two mUC patients treated with ICI who had targeted tumour sequencing were studied. We examined associations between candidate biomarkers and clinical benefit (CB, any objective reduction in tumour size) versus no clinical benefit (NCB, no change or objective increase in tumour size). Both univariable and multivariable analyses for associations were conducted. A comparator cohort of 39 mUC patients treated with taxanes was analysed by using the same methodology. RESULTS: Nine clinical and seven genomic factors correlated with clinical outcomes in univariable analysis in the ICI cohort. Among the 16 factors, neutrophil-to-lymphocyte ratio (NLR) ≥5 (OR = 0.12, 95% CI, 0.01-1.15), visceral metastasis (OR = 0.05, 95% CI, 0.01-0.43) and single-nucleotide variant (SNV) count < 10 (OR = 0.04, 95% CI, 0.006-0.27) were identified as independent predictors of NCB to ICI in multivariable analysis (c-statistic = 0.90). None of the 16 variables were associated with clinical benefit in the taxane cohort. CONCLUSIONS: This three-factor model includes genomic (SNV count >9) and clinical (NLR <5, lack of visceral metastasis) variables predictive for benefit to ICI but not taxane therapy for mUC. External validation of these hypothesis-generating results is warranted to enable use in routine clinical care.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias Urológicas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/antagonistas & inibidores , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/imunologia , Feminino , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Urológicas/genética , Neoplasias Urológicas/imunologia
13.
Nat Med ; 25(10): 1615-1626, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31591588

RESUMO

Oncogenesis is driven by germline, environmental and stochastic factors. It is unknown how these interact to produce the molecular phenotypes of tumors. We therefore quantified the influence of germline polymorphisms on the somatic epigenome of 589 localized prostate tumors. Predisposition risk loci influence a tumor's epigenome, uncovering a mechanism for cancer susceptibility. We identified and validated 1,178 loci associated with altered methylation in tumoral but not nonmalignant tissue. These tumor methylation quantitative trait loci influence chromatin structure, as well as RNA and protein abundance. One prominent tumor methylation quantitative trait locus is associated with AKT1 expression and is predictive of relapse after definitive local therapy in both discovery and validation cohorts. These data reveal intricate crosstalk between the germ line and the epigenome of primary tumors, which may help identify germline biomarkers of aggressive disease to aid patient triage and optimize the use of more invasive or expensive diagnostic assays.


Assuntos
Metilação de DNA/genética , Epigenoma/genética , Mutação em Linhagem Germinativa/genética , Neoplasias da Próstata/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Genoma Humano/genética , Humanos , Masculino , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/genética , Locos de Características Quantitativas/genética
14.
Eur Urol Oncol ; 2(5): 475-482, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31411988

RESUMO

BACKGROUND: PTEN deletion is associated with relapse after therapy for localized prostate cancer. There are limited data on PTEN loss as detected by immunohistochemistry (IHC) and the risk of lethal disease after surgery. OBJECTIVE: To determine whether PTEN loss as detected by quantitative fluorescence IHC (FIHC) predicts lethal disease outcomes after surgery for prostate cancer. DESIGN, SETTING AND PARTICIPANTS: We used formalin-fixed, paraffin-embedded radical prostatectomy specimens to construct tissue microarrays and perform dual FIHC for PTEN and AMACR for masking tumor epithelium, plus semi-quantitative multispectral imaging analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The association of PTEN status analyzed continuously and dichotomously (low [expression in the lowest quartile] vs higher [expression >lowest quartile]) with disease outcomes (metastasis and death) was assessed with adjustment for age, Gleason score, and stage in multivariable analyses. The prognostic ability of PTEN was assessed using logistic regression models. RESULTS AND LIMITATIONS: Low PTEN expression was associated with a higher risk of metastatic disease as both a continuous (hazard ratio [HR] 1.49, 95% confidence interval [CI] 1.14-1.92; p<0.003) and dichotomous (HR 1.92, 95% CI 1.02-3.63; p=0.04) variable. A significant association between low PTEN expression and poorer overall survival was observed (continuous: HR 1.89, 95% CI 1.37-2.63; p<0.001; dichotomous: HR 2.66, 95% CI 1.34-5.28; p=0.005). Addition of PTEN status to clinicopathologic factors (age, Gleason score, and stage) incrementally improved a prognostic model assessing 10-yr outcomes for metastatic disease (area under the curve [AUC] 0.76 vs 0.80) and death (AUC 0.70 vs 0.75). CONCLUSIONS: Low PTEN expression detected by FIHC in primary prostate cancer is an independent prognostic biomarker for metastatic disease and death after definitive therapy. FIHC for PTEN is a viable clinical diagnostic assay in this context. PATIENT SUMMARY: We looked at loss of the PTEN protein in prostate tumors from men treated with surgery. Men with PTEN loss were at higher risk of metastasis and death. Assessing PTEN status may be useful in better determination of the risk of poorer outcomes.


Assuntos
Biomarcadores Tumorais/análise , Recidiva Local de Neoplasia/mortalidade , PTEN Fosfo-Hidrolase/análise , Próstata/patologia , Neoplasias da Próstata/mortalidade , Biomarcadores Tumorais/metabolismo , Estudos de Viabilidade , Imunofluorescência , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Gradação de Tumores , PTEN Fosfo-Hidrolase/metabolismo , Prognóstico , Prostatectomia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Estudos Retrospectivos , Análise Serial de Tecidos
15.
Cancer Discov ; 9(11): 1538-1555, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31466944

RESUMO

Metastatic castration-resistant prostate cancer (CRPC) is a fatal disease, primarily resulting from the transcriptional addiction driven by androgen receptor (AR). First-line CRPC treatments typically target AR signaling, but are rapidly bypassed, resulting in only a modest survival benefit with antiandrogens. Therapeutic approaches that more effectively block the AR-transcriptional axis are urgently needed. Here, we investigated the molecular mechanism underlying the association between the transcriptional coactivator MED1 and AR as a vulnerability in AR-driven CRPC. MED1 undergoes CDK7-dependent phosphorylation at T1457 and physically engages AR at superenhancer sites, and is essential for AR-mediated transcription. In addition, a CDK7-specific inhibitor, THZ1, blunts AR-dependent neoplastic growth by blocking AR/MED1 corecruitment genome-wide, as well as reverses the hyperphosphorylated MED1-associated enzalutamide-resistant phenotype. In vivo, THZ1 induces tumor regression of AR-amplified human CRPC in a xenograft mouse model. Together, we demonstrate that CDK7 inhibition selectively targets MED1-mediated, AR-dependent oncogenic transcriptional amplification, thus representing a potential new approach for the treatment of CRPC. SIGNIFICANCE: Potent inhibition of AR signaling is critical to treat CRPC. This study uncovers a driver role for CDK7 in regulating AR-mediated transcription through phosphorylation of MED1, thus revealing a therapeutically targetable potential vulnerability in AR-addicted CRPC.See related commentary by Russo et al., p. 1490.This article is highlighted in the In This Issue feature, p. 1469.


Assuntos
Subunidade 1 do Complexo Mediador/metabolismo , Fenilenodiaminas/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Pirimidinas/administração & dosagem , Receptores Androgênicos/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Elementos Facilitadores Genéticos , Amplificação de Genes , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Células PC-3 , Fenilenodiaminas/farmacologia , Fosforilação/efeitos dos fármacos , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Pirimidinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
16.
PLoS One ; 14(5): e0216997, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31125336

RESUMO

PURPOSE: Genome-wide-association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) that are associated with an increased risk of breast cancer. Most of these studies were conducted primarily in postmenopausal breast cancer patients. Therefore, we set out to assess whether or not these breast cancer variants are also associated with an elevated risk of breast cancer in young premenopausal patients. METHODS: In 451 women of European ancestry who had prospectively enrolled in a longitudinal cohort study for women diagnosed with breast cancer at or under age 40, we genotyped 44 SNPs that were previously associated with breast cancer risk. A control group was comprised of 1142 postmenopausal healthy women from the Nurses' Health Study (NHS). We assessed if the frequencies of the adequately genotyped SNPs differed significantly (p≤0.05) between the cohort of young breast cancer patients and postmenopausal controls, and then we corrected for multiple testing. RESULTS: Genotyping of the controls or cases was inadequate for comparisons between the groups for seven of the 44 SNPs. 9 of the remaining 37 were associated with breast cancer risk in young women with a p-value <0.05: rs10510102, rs1219648, rs13387042, rs1876206, rs2936870, rs2981579, rs3734805, rs3803662 and rs4973768. The directions of these associations were consistent with those in postmenopausal women. However, after correction for multiple testing (Benjamini Hochberg) none of the results remained statistically significant. CONCLUSION: After correction for multiple testing, none of the alleles for postmenopausal breast cancer were clearly associated with risk of premenopausal breast cancer in this relatively small study.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Adulto , Alelos , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Receptores Estrogênicos/genética , Fatores de Risco
17.
J Med Internet Res ; 21(5): e12044, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-31045501

RESUMO

BACKGROUND: The pace of drug discovery and approvals has led to expanding treatments for cancer patients. Although extensive research exists regarding barriers to enrollment in oncology clinical trials, there are limited studies evaluating processes to optimize patient education, oral anticancer therapy administration, and adherence for patients enrolled in clinical trials. In this study, we assess the feasibility of a video-based, personalized webpage for patients enrolled in genitourinary oncology clinical trials involving 1 or more oral anticancer therapy. OBJECTIVE: The primary objective of this trial was to assess the differences in the number of patient-initiated violations in the intervention arm compared with a control arm over 4 treatment cycles. Secondary objectives included patient satisfaction, frequently asked questions by patients on the intervention arm, patient-initiated calls to study team members, and patient-reported stress levels. METHODS: Eligible patients enrolling on a therapeutic clinical trial for a genitourinary malignancy were randomized 2:1 to the intervention arm or control arm. Patients randomized to the intervention arm received access to a video-based, personalized webpage, which included videos of patients' own clinic encounters with their providers, instructional videos on medication administration and side effects, and electronic versions of educational documents. RESULTS: A total of 99 patients were enrolled (89 were evaluable; 66 completed 4 cycles). In total, 71% (40/56) of patients in the intervention arm had 1 or more patient-initiated violation compared with 70% (23/33) in the control arm. There was no difference in the total number of violations across 4 cycles between the 2 arms (estimate=-0.0939, 95% CI-0.6295 to 0.4418, P value=.73). Median baseline satisfaction scores for the intervention and control arms were 72 and 73, respectively, indicating high levels of patient satisfaction in both arms. Median baseline patient-reported stress levels were 10 and 13 for the intervention and control arms, respectively, indicating low stress levels in both arms at baseline. CONCLUSIONS: This study is among the first to evaluate a video-based, personalized webpage that provides patients with educational videos and video recordings of clinical trial appointments. Despite not meeting the primary endpoint of reduced patient-initiated violations, this study demonstrates the feasibility of a video-based, personalized webpage in clinical trials. Future research assessing this tool might be better suited for realms outside of clinical trials and might consider the use of an endpoint that assesses patient-reported outcomes directly. A major limitation of this study was the lack of prior data for estimating the null hypothesis in this population.


Assuntos
Neoplasias Urogenitais/epidemiologia , Gravação em Vídeo/métodos , Feminino , Humanos , Internet , Masculino
18.
Clin Cancer Res ; 25(14): 4480-4492, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-30996073

RESUMO

PURPOSE: Defects in genes in the DNA repair pathways significantly contribute to prostate cancer progression. We hypothesize that overexpression of DNA repair genes may also drive poorer outcomes in prostate cancer. The ribonucleotide reductase small subunit M2 (RRM2) is essential for DNA synthesis and DNA repair by producing dNTPs. It is frequently overexpressed in cancers, but very little is known about its function in prostate cancer. EXPERIMENTAL DESIGN: The oncogenic activity of RRM2 in prostate cancer cells was assessed by inhibiting or overexpressing RRM2. The molecular mechanisms of RRM2 function were determined. The clinical significance of RRM2 overexpression was evaluated in 11 prostate cancer clinical cohorts. The efficacy of an RRM2 inhibitor (COH29) was assessed in vitro and in vivo. Finally, the mechanism underlying the transcriptional activation of RRM2 in prostate cancer tissue and cells was determined. RESULTS: Knockdown of RRM2 inhibited its oncogenic function, whereas overexpression of RRM2 promoted epithelial mesenchymal transition in prostate cancer cells. The prognostic value of RRM2 RNA levels in prostate cancer was confirmed in 11 clinical cohorts. Integrating the transcriptomic and phosphoproteomic changes induced by RRM2 unraveled multiple oncogenic pathways downstream of RRM2. Targeting RRM2 with COH29 showed excellent efficacy. Thirteen putative RRM2-targeting transcription factors were bioinformatically identified, and FOXM1 was validated to transcriptionally activate RRM2 in prostate cancer. CONCLUSIONS: We propose that increased expression of RRM2 is a mechanism driving poor patient outcomes in prostate cancer and that its inhibition may be of significant therapeutic value.


Assuntos
Biomarcadores Tumorais/metabolismo , Proliferação de Células , Reparo do DNA , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata/patologia , Ribonucleosídeo Difosfato Redutase/metabolismo , Animais , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Células Cultivadas , Estudos de Coortes , Proteína Forkhead Box M1/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Prognóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Ribonucleosídeo Difosfato Redutase/genética , Taxa de Sobrevida , Ativação Transcricional , Transcriptoma , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Brachytherapy ; 18(2): 198-203, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30638910

RESUMO

PURPOSE: Although current Delphi Consensus guidelines do not recommend a specific definition of biochemical recurrence after partial gland therapy, these guidelines acknowledge that serial prostate-specific antigen (PSA) tests remain the best marker for monitoring disease after treatment. The purpose of this study was to determine whether PSA velocity at failure per the Phoenix (nadir + 2 ng/mL) definition is associated with metastasis and prostate cancer-specific mortality (PCSM) in a cohort of patients who experienced PSA failure after partial gland therapy. METHODS: Between 1997 and 2007, 285 patients with favorable risk prostate cancer underwent partial prostate brachytherapy to the peripheral zone. PSA velocity was calculated for 94 patients who experienced PSA failure per the Phoenix (nadir + 2) definition. Fine and Gray competing risks regression was performed to determine whether PSA velocity and other clinical factors were associated with metastasis and PCSM. RESULTS: The median time to PSA failure was 4.2 years (interquartile range: 2.2, 7.9), and the median followup time after PSA failure was 6.5 years (3.5-9.7). Seventeen patients developed metastases, and five experienced PCSM. On multivariate analysis, PSA velocity ≥3.0 ng/mL/year (adjusted hazard ratio 5.97; [2.57, 13.90]; p < 0.001) and PSA nadir (adjusted hazard ratio 0.39; [0.24, 0.64]; p < 0.001) were significantly associated with metastasis. PSA velocity ≥3.0 ng/mL/year was also associated with PCSM (HR 15.3; [1.8, 128.0]; p = 0.012) on univariate analysis. CONCLUSIONS: Rapid PSA velocity at PSA failure after partial gland treatment may be prognostic for long-term outcomes.


Assuntos
Braquiterapia , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/radioterapia , Idoso , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia , Prognóstico , Modelos de Riscos Proporcionais , Antígeno Prostático Específico/uso terapêutico , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Estudos Retrospectivos , Taxa de Sobrevida
20.
Prostate ; 79(1): 73-80, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30141208

RESUMO

BACKGROUND: We previously identified a blood RNA transcript-based model consisting of six immune or inflammatory response genes (ABL2, SEMA4D, ITGAL, C1QA, TIMP1, and CDKN1A) that was prognostic for survival in cohorts of men with castration-resistant prostate cancer (CRPC). We investigated whether inherited variation in these six genes was associated with overall survival (OS) in men with CRPC. METHODS: The test cohort comprised 600 patients diagnosed with CRPC between 1996 and 2011 at Dana-Farber Cancer Institute. Genotyping of 66 tagging single nucleotide polymorphisms (SNPs) spanning the six genes was performed on blood derived DNAs. For the top four SNPs (P < 0.05), validation was conducted in an independent cohort of 223 men diagnosed with CRPC between 2000 and 2014. Multivariable Cox regression adjusting for known prognostic factors estimated hazard ratios (HR) and 95% confidence intervals (CI) of the association of genetic variants with OS. RESULTS: Two thirds of patients in both cohorts had metastases at CRPC diagnosis. Median OS from CRPC diagnosis was 3.6 (95%CI 3.3-4.0) years in the test cohort and 4.6 (95%CI 3.8-5.2) years in the validation cohort. Fifty-nine SNPs in Hardy-Weinberg equilibrium were analyzed. The major alleles of rs1318056 and rs1490311 in ABL2, and the minor alleles of rs2073917 and rs3764322 in ITGAL were associated with increased risk of death in the test cohort (adjusted-HRs 1.27-1.39; adjusted-p <0.05; false discovery rate <0.35). In the validation cohort, a similar association with OS was observed for rs1318056 in ABL2 (adjusted-HR 1.44; 95%CI 0.89-2.34) and rs2073917 in ITGAL (adjusted-HR 1.41; 95%CI 0.82-2.42). The associations did not reach statistical significance most likely due to the small sample size of the validation cohort (adjusted-p = 0.142 and 0.209, respectively). Additional eQTL analysis indicated that minor alleles of rs1318056 and rs1490311 in ABL2 are associated with a lower ABL2 expression in blood. CONCLUSIONS: These findings corroborate our initial work on the RNA expression of genes involved in immunity and inflammation from blood and clinical outcome and suggest that germline polymorphisms in ABL2 and ITGAL may be associated with the risk of death in men with CRPC. Further studies are needed to validate these findings and to explore their functional mechanisms.


Assuntos
Estudos de Associação Genética/métodos , Variação Genética/genética , Polimorfismo de Nucleotídeo Único/genética , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/mortalidade , Idoso , Estudos de Coortes , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Taxa de Sobrevida/tendências
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