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1.
Eur Urol Oncol ; 2019 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-31412004

RESUMO

Cell-free circulating DNA (cfDNA) can be used for noninvasive profiling of tumor genomic aberrations. We hypothesized that molecular alterations may inform prognostication in advanced urothelial carcinoma (aUC). We evaluated 124 aUC patients who underwent cfDNA analysis using a 73-gene sequencing panel (Guardant360). The association of molecular alterations and clinical factors with overall survival (OS) and failure-free-survival (FFS) was evaluated using the Kaplan-Meier method and Cox proportional-hazards regression. The median age was 72yr, and 65 patients (52.4%) received prior therapy with platinum, 21 (17.1%) with a taxane, and ten (8.1%) with a PD-1/PD-L1 inhibitor. At least one genomic alteration was detected in 112 patients (90.3%). The median number of alterations per sample was four (range 0-80). Commonly altered genes included TP53 (54.8%), PIK3CA (24.2%), ARID1A (22.6%), ERBB2 (19.4%), EGFR (16.1%), NF1 (13.7%), RB1 (12.9%), FGFR3 (11.3%), BRAF (10.5%), BRCA1 (10.5%), and RAF1 (8.9%). BRCA1 and RAF1 alterations were associated with worse OS (hazard ratio [HR] 2.48; p=0.07; HR 4.87; p=0.007) and FFS (HR 2.35; p=0.016; HR 2.40; p=0.047). Poor Eastern Cooperative Oncology Group performance status and the presence of visceral metastasis were associated with shorter OS; genomic evolution was observed. In conclusion, cfDNA molecular alterations were detected in most aUC patients. BRCA1 and RAF1 alterations were negatively prognostic, supporting further evaluation of DNA damage response and RAF kinase inhibitors. PATIENT SUMMARY: Noninvasive testing of cell-free circulating DNA in advanced urothelial carcinoma identifies clinically relevant molecular aberrations. Alterations in BRCA1 and RAF1 genes appear to be negatively associated with clinical outcomes, supporting further study of DNA damage response and RAF kinase inhibitors in selected patients.

2.
J Immunother Cancer ; 7(1): 139, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138299

RESUMO

BACKGROUND: The tumor immune microenvironment has become the focus of research in clear cell renal cell carcinoma (ccRCC) due to its important role in immune surveillance post nephrectomy. This study investigates the correlation of tumor infiltrating immune cell characteristics with rates of recurrence following surgery in localized ccRCC. METHODS: We morphologically identified and scored tumor infiltrating lymphocytes (TILs) in hematoxylin and eosin (H&E) stained slides of patients with localized ccRCC (stage ≥T1b excluding stage IV). The University of Alabama at Birmingham (UAB) dataset (n = 159) was used to discover and the Fox Chase Cancer Center (FCCC) dataset (n = 198) was used to validate the results of morphologic immune cell analysis. We then performed gene expression analysis using the Immune Profile panel by NanoString in the UAB cohort and identified immune cells and pathways associated with recurrence, followed by validation in the Cancer Genome Atlas (TCGA) ccRCC dataset. Infiltrating immune cell types were identified by gene expression deconvolution. RESULTS: The presence of TILs identified by morphology correlated with higher T cell, Th1, CD8+ T and Treg gene signatures. Recurrence was associated with lower T cells and higher neutrophils. Higher Teffector (Teff)/Treg ratio correlated with lower rate of recurrence and was validated in the TCGA dataset. Genes associated with adaptive immune response were downregulated in tumors that recurred. Unsupervised hierarchical clustering identified a subset of patients with over-expression of adaptive response genes including CD8, CD3, GZMA/B, PRF1, IDO1, CTLA4, PDL1, ICOS and TIGIT. These patients had higher morphologic lymphocyte infiltration and T cell gene expression. Higher levels of TILs identified by morphology correlated with higher rates of recurrence in our discovery dataset but not in our validation set. CONCLUSIONS: Recurrence of ccRCC following surgery was associated with lower T cell infiltrate, lower adaptive immune response and higher neutrophil gene expression. Presence of higher Teff/Treg ratio correlated with lower recurrence.

3.
Cancer Res ; 79(7): 1413-1425, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30733194

RESUMO

Although c-MYC and mTOR are frequently activated proteins in prostate cancer, any interaction between the two is largely untested. Here, we characterize the functional cross-talk between FOXP3-c-MYC and TSC1-mTOR signaling during tumor progression. Deletion of Tsc1 in mouse embryonic fibroblasts (MEF) decreased phosphorylation of c-MYC at threonine 58 (pT58) and increased phosphorylation at serine 62 (pS62), an observation validated in prostate cancer cells. Conversely, inhibition of mTOR increased pT58 but decreased pS62. Loss of both FOXP3 and TSC1 in prostate cancer cells synergistically enhanced c-MYC expression via regulation of c-Myc transcription and protein phosphorylation. This crosstalk between FOXP3 and TSC1 appeared to be mediated by both the mTOR-4EBP1-c-MYC and FOXP3-c-MYC pathways. In mice, Tsc1 and Foxp3 double deletions in the prostate led to prostate carcinomas at an early age; this did not occur in these mice with an added c-Myc deletion. In addition, we observed synergistic antitumor effects of cotreating mice with inhibitors of mTOR and c-MYC in prostate cancer cells and in Foxp3 and Tsc1 double-mutant mice. In human prostate cancer, loss of nuclear FOXP3 is often accompanied by low expression of TSC1. Because loss of FOXP3 transcriptionally induces c-Myc expression and loss of TSC1 activates mTOR signaling, these data suggest cross-talk between FOXP3-c-MYC and TSC1-mTOR signaling that converges on c-MYC to regulate tumor progression. Coadministration of c-MYC and mTOR inhibitors may overcome the resistance to mTOR inhibition commonly observed in prostate cancer cells. SIGNIFICANCE: These results establish the principle of a synergistic action of TSC1 and FOXP3 during prostate cancer progression and provide new therapeutic targets for patients who have prostate cancer with two signaling defects.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/7/1413/F1.large.jpg.

4.
Cancer ; 125(9): 1459-1469, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30620391

RESUMO

BACKGROUND: Because cell-free DNA (cfDNA) analysis facilitates the noninvasive genomic profiling of metastatic castration-resistant prostate cancer (mCRPC), the authors evaluated the association between cfDNA alterations and outcomes and evolution with therapy. METHODS: Patients with mCRPC underwent cfDNA genomic profiling using Guardant360, which examines major cancer-associated genes. Clinical factors, therapy information, failure-free survival, and overall survival (OS) were obtained for select patients. The association between genomic alterations and outcomes was investigated. RESULTS: Of 514 men with mCRPC, 482 (94%) had ≥1 circulating tumor DNA (ctDNA) alteration. The most common recurrent somatic mutations were in TP53 (36%), androgen receptor (AR) (22%), adenomatous polyposis coli (APC) (10%), neurofibromin 1 (NF1) (9%), epidermal growth factor receptor (EGFR), catenin beta-1 (CTNNB1), and AT-rich interactive domain-containing protein 1A (ARID1A) (6% each); and BRCA1, BRCA2, and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (5% each) The most common genes with increased copy numbers were AR (30%), MYC (20%), and BRAF (18%). Clinical outcomes were available for 163 patients, 46 of whom (28.8%) were untreated for mCRPC. A higher number of ctDNA alterations, AR alterations, and amplifications of MYC and BRAF were associated with worse failure-free survival and/or OS. On multivariable analysis, MYC amplification remained significantly associated with OS. Prior therapy and serial profiling demonstrated the evolution of alterations in AR and other genes. CONCLUSIONS: ctDNA frequently was detected in this large cohort of "real-world" patients with mCRPC, and the alterations appeared to be similar to previously reported tumor tissue alterations. A higher number of alterations, and AR and MYC alterations, appear to compromise clinical outcomes, suggesting a role for immune checkpoint inhibitors and novel AR and BET inhibitors in selected patients.

5.
Mol Cancer Res ; 2018 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-30131446

RESUMO

The Cancer Genome Atlas (TCGA) and other large-scale genomic data pipelines have been integral to the current understanding of the molecular events underlying renal cell carcinoma (RCC). These data networks have focused mostly on primary RCC, which often demonstrates indolent behavior. However, metastatic disease is the major cause of mortality associated with RCC and data sets examining metastatic tumors are sparse. Therefore, a more comprehensive analysis of gene expression and DNA methylome profiling of metastatic RCC in addition to primary RCC and normal kidney was performed. Integrative analysis of the methylome and transcriptome identified over 30 RCC-specific genes whose mRNA expression inversely correlated with promoter methylation, including several known targets of hypoxia inducible factors. Notably, genes encoding several metabolism-related proteins were identified as differentially regulated via methylation including hexokinase 2, aldolase C, stearoyl-CoA desaturase, and estrogen-related receptor-γ (ESRRG), which has a known role in the regulation of nuclear-encoded mitochondrial metabolism genes. Several gene expression changes could portend prognosis in the TCGA cohort. Mechanistically, ESRRG loss occurs via DNA methylation and histone repressive silencing mediated by the polycomb repressor complex 2. Restoration of ESRRG in RCC lines suppresses migratory and invasive phenotypes independently of its canonical role in mitochondrial metabolism.Implications: Collectively, these data provide significant insight into the biology of aggressive RCC and demonstrate a novel role for DNA methylation in the promotion of HIF signaling and invasive phenotypes in renal cancer. Mol Cancer Res; 1-13. ©2018 AACR.

6.
J Oncol Pract ; 14(6): e384-e392, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29750578

RESUMO

Therapeutic trials represent the front line of clinical progress, where the rubber meets the road. The conduct of clinical trials requires unique skills, innate as well as learned, on the part of the investigators who conduct these studies. Often such skills are acquired on the job and are passed on from mentor to junior investigator. However, over the years, the role of the principal investigator (PI) has evolved into a vast list of roles and responsibilities that cannot readily be conveyed through a hands-on approach alone. The fast-paced tempo of drug discovery and development, and the ever-increasing numbers of therapeutic trials being conducted in the United States, combined with a decline in the number of new clinical investigators, have exposed a gap between the expectations placed on the PI and the training and experience of today's young clinicians, who are being asked to take on the responsibilities outlined in Food and Drug Administration Form 1572. This article aims to begin an exploration of the role and increasing responsibilities of a PI and the growing need for structured investigator training. We propose options to better equip the PI to achieve compliance with Good Clinical Practice.

7.
Cancer ; 124(10): 2115-2124, 2018 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-29517810

RESUMO

BACKGROUND: Biomarker-guided clinical trials are increasingly common in metastatic urothelial carcinoma (mUC), yet patients for whom contemporary tumor tissue is not available are not eligible. Technological advancements in sequencing have made cell-free circulating DNA (cfDNA) next-generation sequencing (NGS) readily available in the clinic. The objective of the current study was to determine whether the genomic profile of mUC detected by NGS of cfDNA is similar to historical tumor tissue NGS studies. A secondary objective was to determine whether the frequency of genomic alterations (GAs) differed between lower tract mUC (mLTUC) and upper tract mUC (mUTUC). METHODS: Patients from 13 academic medical centers in the United States who had a diagnosis of mUC between 2014 and 2017 and for whom cfDNA NGS results were available were included. cfDNA profiling was performed using a commercially available platform (Guardant360) targeting 73 genes. RESULTS: Of 369 patients with mUC, 294 were diagnosed with mLTUC and 75 with mUTUC. A total of 2130 GAs were identified in the overall mUC cohort: 1610 and 520, respectively, in the mLTUC and mUTUC cohorts. In the mLTUC cohort, frequently observed GAs were similar between cfDNA NGS and historical tumor tissue studies, including tumor protein p53 (TP53) (P = 1.000 and .115, respectively), AT-rich interaction domain 1A (ARID1A) (P = .058 and .058, respectively), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (P = .058 and .067, respectively), erb-b2 receptor tyrosine kinase 2 (ERBB2) (P = .565 and .074, respectively), and fibroblast growth factor receptor 3 (FGFR3) (P = .164 and .014, respectively). No significant difference was observed with regard to the frequency of GAs between patients with mLTUC and mUTUC. CONCLUSIONS: Among patients with mUC for whom no tumor tissue was available, cfDNA NGS was able to identify a similar profile of GAs for biomarker-driven clinical trials compared with tumor tissue. Despite the more aggressive clinical course, cases of mUTUC demonstrated a circulating tumor DNA genomic landscape that was similar to that of mLTUC. Cancer 2018;124:2115-24. © 2018 American Cancer Society.

8.
Cancer Causes Control ; 29(3): 333-342, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29429013

RESUMO

BACKGROUND: This study examines whether racial disparities in hospitalization outcomes persist between African-American and White women with ovarian cancer after matching on demographic, presentation, and treatment factors. METHODS: Using data from the Nationwide Inpatient Sample database, 5,164 African-American ovarian cancer patients were sequentially matched with White patients on demographic (e.g., age, income), presentation (e.g., stage, comorbidities), and treatment (e.g., surgery, radiation) factors. Racial differences in-hospital length of stay, post-operative complications, and in-hospital mortality were evaluated using conditional logistic regression models. RESULTS: White ovarian cancer patients had relatively higher odds of post-operative complications when matched on demographics (OR 1.35, 95% CI 1.05, 1.74), and presentation (OR 1.28, 95% CI 1.00, 1.65) but not when additionally matched on treatment (OR 1.03, 95% CI 0.78, 1.35). African-American patients had longer in-hospital length of stay (6.96 ± 7.21 days) compared with White patients when matched on demographics (6.37 ± 7.07 days), presentation (6.48 ± 7.16 days), and treatment (6.53 ± 7.59 days). Compared with African-American patients, White patients experienced lower odds of in-hospital mortality when matched on demographics (OR 0.78, 95% CI 0.66, 0.92), but this disparity was no longer significant when additionally matched on presentation (OR 0.88, 95% CI 0.75, 1.04) and treatment (OR 0.95, 95% CI 0.81, 1.12). CONCLUSION: Racial disparities in ovarian cancer hospitalization outcomes persisted after adjusting for demographic and presentation factors; however these differences were eliminated after additionally accounting for treatment factors. More studies are needed to determine the factors driving racial differences in ovarian cancer treatment in otherwise similar patient populations.

9.
Curr Treat Options Oncol ; 19(1): 2, 2018 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-29349592

RESUMO

OPINION STATEMENT: High-risk localized renal cell carcinoma represents a therapeutic challenge with high recurrence rates and poor survival with nephrectomy alone. Multiple agents targeting angiogenic and immunologic pathways have demonstrated remarkable efficacy in the metastatic setting but have failed to replicate similar successes in localized disease. Study results with adjuvant anti-angiogenic therapies may have been compromised by the high incidence of treatment discontinuations or dosage reductions secondary to intolerable side effects. Improving patient selection could play a major role in improving outcomes. Multiple models exist to predict survival but require improved accuracy in identifying recurrence to justify exposing patients to therapies that could significantly impair quality of life. Further understanding of pathological and molecular mechanisms of recurrence is required. Novel tools like gene recurrence scores are emerging to improve prognostication for patient selection. Immunotherapeutic approaches using check point inhibition have the potential to achieve sustained remissions with a significantly improved toxicity profile. Amplifying the immune response with a combination of neoadjuvant and adjuvant therapy to exploit the larger antigenic burden prior to nephrectomy has the biologic potential for making significant improvements in efficacy.

10.
Cancer Epidemiol ; 49: 138-143, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28623836

RESUMO

BACKGROUND: The purpose of this study is to determine if racial disparities in inpatient outcomes persist among hospitalized patients comparing African American and White breast cancer patients matched on demographics, presentation and treatment. METHODS: A total of 136,211 African American and White breast cancer patients from the Healthcare Cost and Utilization Project - Nationwide Inpatient Sample (HCUP-NIS) database, matched on demographics alone, demographics and presentation or demographics, presentation and treatment were studied. Conditional logistic regression was conducted to evaluate post-surgical complications, length of stay and in-hospital mortality outcomes. Analysis was further stratified by age (≤65 years and >65years) to evaluate whether disparities were larger in younger or older patients. All analysis was conducted using SAS 9.3. RESULTS: White women had significantly shorter hospital length of stay when matched on demographics (ß=-0.87, p-value=<0.0001), demographics and presentation (ß=-0.63, p-value=<0.0001), and demographics, presentation and treatment (ß=-0.51, p-value=<0.0001) compared with African Americans. White women also had lower odds of mortality compared with African American women when matched on demographics (OR: 0.72, 95% CI: 0.65-0.79), demographics and presentation (OR: 0.77, 95% CI: 0.71-0.85), or matched on demographics, presentation and treatment (OR: 0.80, 95% CI: 0.73-0.88). The racial difference observed in length of stay and mortality was larger in the age group ≤65 years compared with >65years CONCLUSION: African American women experienced higher odds of inpatient mortality and longer length of stay compared with White women even after accounting for differences in demographics, presentation and treatment characteristics.


Assuntos
Afro-Americanos/estatística & dados numéricos , Neoplasias da Mama/etnologia , Neoplasias da Mama/mortalidade , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Disparidades em Assistência à Saúde/estatística & dados numéricos , Idoso , Neoplasias da Mama/terapia , Feminino , Mortalidade Hospitalar , Hospitalização/estatística & dados numéricos , Humanos , Tempo de Internação , Modelos Logísticos , Pessoa de Meia-Idade , Estados Unidos/epidemiologia
11.
Clin Genitourin Cancer ; 15(5): 534-539, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28526418

RESUMO

BACKGROUND: Because of the low historical prevalence of measurable disease in metastatic castration-resistant prostate cancer (mCRPC), phase II trials have used prostate-specific antigen (PSA) and bone scan changes as primary end points. Frequent whole-body imaging and improved computed tomography technology currently identify measurable disease more frequently, warranting consideration of objective response as a major end point. PATIENTS AND METHODS: Data from reported phase III trials of mCRPC were analyzed. The proportion of patients with measurable disease, setting (pre-docetaxel [D], D-based, post-D), year of starting accrual, PSA, and the requirement for symptoms were collected. The χ2 test was used to evaluate the association of variables with measurable disease rate. RESULTS: Twenty phase III trials totaling 19,276 men with mCRPC were evaluable. Three trials (n = 1289) started accruing before 2000 and 17 trials (n = 17,987) accrued after 2000. The proportion of measurable disease rate for all trials was 47.5%. The measurable disease rate was significantly higher (P < .001) in trials that accrued after 2000 versus before 2000 (48.7% vs. 31.1%; P < .001), D-based (51.8%) or post-D patients (48.9%) compared with pre-D patients (38.6%) and in trials allowing symptomatic versus asymptomatic/minimally symptomatic patients (50.1% vs. 40.0%). CONCLUSION: The proportion of men with measurable disease was significantly higher in phase III trials of mCRPC that accrued after 2000, in D-based or post-D patients and in trials that allowed symptomatic patients. Because of the association of objective measurable changes with survival, Response Evaluation Criteria in Solid Tumors changes might warrant consideration as a major end point in phase II trials to obtain a firm signal of efficacy before launching phase III trials.


Assuntos
Antígeno Prostático Específico/metabolismo , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/epidemiologia , Ensaios Clínicos como Assunto , Humanos , Masculino , Metástase Neoplásica , Prevalência , Neoplasias de Próstata Resistentes à Castração/metabolismo , Tomografia Computadorizada por Raios X , Imagem Corporal Total/métodos
12.
Oncotarget ; 8(13): 21710-21718, 2017 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-28423512

RESUMO

Penile squamous cell carcinoma (PSCC) is an orphan malignancy with poorly understood biology and suboptimal systemic therapy. Given that kinases may be drivers and readily actionable, we performed comprehensive multiplatform analysis of kinases in PSCC tumor and normal tissue. Fresh frozen tumors were collected from 11 patients with PSCC. After macrodissection to demarcate tumor from normal tissue, the samples underwent multiplatform analysis of kinases. Next Generation Sequencing (NGS) of 517 kinase genes was performed using Agilent Kinome capture and run on the Illumina MiSeq at PE150bp. The NanoString nCounter® platform analyzed the expression of 519 kinase genes. Kinase activity of tissue lysates was measured using PamStation®12 high-content phospho-peptide substrate microarray system. Network mapping was done with GeneGo MetaCore™ and upstream kinase prediction was performed with BioNavigator and the Kinexus database. Ingenuity pathway analysis was performed to integrate elevated kinase activity and gene over-expression with coexisting missense mutations at DNA level. Top pathways upregulated in both the kinase activity and gene expression platforms were PTEN, STAT3, GNRH, IL-8 and B cell receptor signaling. Potentially relevant missense mutations were seen in 176 kinase genes, with the top altered pathways overlapping with gene overexpression being GNRH, NF-kB and STAT3 signaling. ERBB2, ERBB3 and SYK were altered on NGS and also exhibited elevated kinase activity. To summarize, multiplatform comprehensive analysis of kinases discovered potential drivers of PSCC and actionable therapeutic targets. Translational studies are necessary to validate the functional relevance of our data to make advances in this rare malignancy.


Assuntos
Carcinoma de Células Escamosas/enzimologia , Neoplasias Penianas/enzimologia , Proteínas Quinases/análise , Idoso , Carcinoma de Células Escamosas/patologia , Biologia Computacional , Análise Mutacional de DNA , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Neoplasias Penianas/patologia , Proteínas Quinases/genética , Transcriptoma
13.
Oncotarget ; 8(17): 29220-29232, 2017 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-28418903

RESUMO

The introduction of targeted therapies has caused a paradigm shift in the treatment of metastatic clear cell (cc)-renal cell carcinoma (RCC). We hypothesized that determining differential kinase activity between primary and metastatic tumor sites may identify critical drivers of progression and relevant therapeutic targets in metastatic disease. Kinomic profiling was performed on primary tumor and metastatic tumor deposits utilizing a peptide substrate microarray to detect relative tyrosine phosphorylation activity. Pharmacologic and genetic loss of function experiments were used to assess the biologic significance of the top scoring kinase on in vitro and in vivo tumor phenotypes. Kinomics identified 7 peptides with increased tyrosine phosphorylation in metastases that were significantly altered (p<0.005). Based on these peptides, bioinformatics analyses identified several candidate kinases activated in metastases compared to primary tumors. The highest ranked upstream kinase was Focal Adhesion Kinase 1 (FAK1). RCC lines demonstrate evidence of elevated FAK1 activation relative to non-transformed renal epithelial cells. Pharmacologic inhibition of FAK1 with GSK2256098 suppresses in vitro tumor phenotypes. In turn, FAK1 knockdown in RCC cells suppresses both in vitro phenotypes and in vivo tumor growth. Collectively, these data demonstrate functional activation of FAK1 in metastases and provide preclinical rationale for targeting this kinase in the setting of advanced ccRCC.


Assuntos
Carcinoma de Células Renais/genética , Perfilação da Expressão Gênica/métodos , Linhagem Celular Tumoral , Quinase 1 de Adesão Focal/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos
14.
FASEB J ; 31(4): 1608-1619, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28069826

RESUMO

Androgen-deprivation therapy has been identified to induce oxidative stress in prostate cancer (PCa), leading to reactivation of androgen receptor (AR) signaling in a hormone-refractory manner. Thus, antioxidant therapies have gained attention as adjuvants for castration-resistant PCa. Here, we report for the first time that human endostatin (ES) prevents androgen-independent growth phenotype in PCa cells through its molecular targeting of AR and glucocorticoid receptor (GR) and downstream pro-oxidant signaling. This reversal after ES treatment significantly decreased PCa cell proliferation through down-regulation of GR and up-regulation of manganese superoxide dismutase and reduced glutathione levels. Proteome and biochemical analyses of ES-treated PCa cells further indicated a significant up-regulation of enzymes in the major reactive oxygen species (ROS) scavenging machinery, including catalase, glutathione synthetase, glutathione reductase, NADPH-cytochrome P450 reductase, biliverdin reductase, and thioredoxin reductase, resulting in a concomitant reduction of intracellular ROS. ES further augmented the antioxidant system through up-regulation of glucose influx, the pentose phosphate pathway, and NAD salvaging pathways. This shift in cancer cell redox homeostasis by ES significantly decreased the effect of protumorigenic oxidative machinery on androgen-independent PCa growth, suggesting that ES can suppress GR-induced resistant phenotype upon AR antagonism and that the dual targeting action of ES on AR and GR can be further translated to PCa therapy.-Lee, J. H., Kang, M., Wang, H., Naik, G., Mobley, J. A., Sonpavde, G., Garvey, W. T., Darley-Usmar, V. M., Ponnazhagan, S. Endostatin inhibits androgen-independent prostate cancer growth by suppressing nuclear receptor-mediated oxidative stress.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Endostatinas/farmacologia , Estresse Oxidativo , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Catalase/genética , Catalase/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Glutationa Redutase/genética , Glutationa Redutase/metabolismo , Humanos , Masculino , NADPH-Ferri-Hemoproteína Redutase/genética , NADPH-Ferri-Hemoproteína Redutase/metabolismo , Receptores de Glucocorticoides/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Tiorredoxina Dissulfeto Redutase/genética , Tiorredoxina Dissulfeto Redutase/metabolismo
15.
Cancer Epidemiol ; 46: 73-79, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28056390

RESUMO

OBJECTIVES: This paper aims to determine whether racial disparities exist in hospitalization outcomes among African-American and White hospitalized prostate cancer patients in the United States. We evaluated racial differences among matched groups of patients in post-operative complications, hospital length of stay and in-hospital mortality. METHODS: We identified a total of 183,856 men aged 40 years and older with a primary diagnosis of prostate cancer, of which 58,701 underwent prostatectomy, through the Nationwide Inpatient Sample, and matched all African-American patients with White patients on: 1) Demographics, 2) Demographics+Clinical presentation and 3) Demographics+Clinical presentation+Treatment. Multivariable regression analyses were conducted in SAS and estimates were reported with 95% confidence intervals. RESULTS: African-American patients were more likely to be admitted with metastatic disease (24.8%) compared with White patients matched on demographics (17.9%), and demographics+presentation (23.6%). However, 23.9% of African-American patients received surgery compared with 38.2% and 34.2% of Whites matched on demographics and demographics+presentation, respectively. White patients had lower in-hospital mortality compared with African-American patients matched on demographics (OR: 0.72, 95% CI: 0.66-0.79), demographics+presentation (OR: 0.88, 95% CI: 0.81-0.96), but was no longer significantly lower when matched on demographics, presentation and treatment (OR: 0.92, 95% CI: 0.85-1.00). CONCLUSION: There were significant racial differences in outcomes among prostate cancer patients within the inpatient setting, even after accounting for demographic and presentation differences.


Assuntos
Disparidades em Assistência à Saúde/tendências , Neoplasias da Próstata/terapia , Adulto , Afro-Americanos , Idoso , Grupos de Populações Continentais , Grupo com Ancestrais do Continente Europeu , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia
16.
PLoS One ; 11(8): e0160924, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27574806

RESUMO

Kinases are therapeutically actionable targets. Kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFR) and mammalian target of rapamycin (mTOR) improve outcomes in metastatic clear cell renal cell carcinoma (ccRCC), but are not curative. Metastatic tumor tissue has not been comprehensively studied for kinase gene expression. Paired intra-patient kinase gene expression analysis in primary tumor (T), matched normal kidney (N) and metastatic tumor tissue (M) may assist in identifying drivers of metastasis and prioritizing therapeutic targets. We compared the expression of 519 kinase genes using NanoString in T, N and M in 35 patients to discover genes over-expressed in M compared to T and N tissue. RNA-seq data derived from ccRCC tumors in The Cancer Genome Atlas (TCGA) were used to demonstrate differential expression of genes in primary tumor tissue from patients that had metastasis at baseline (n = 79) compared to those that did not develop metastasis for at least 2 years (n = 187). Functional analysis was conducted to identify key signaling pathways by using Ingenuity Pathway Analysis. Of 10 kinase genes overexpressed in metastases compared to primary tumor in the discovery cohort, 9 genes were also differentially expressed in TCGA primary tumors with metastasis at baseline compared to primary tumors without metastasis for at least 2 years: EPHB2, AURKA, GSG2, IKBKE, MELK, CSK, CHEK2, CDC7 and MAP3K8; p<0.001). The top pathways overexpressed in M tissue were pyridoxal 5'-phosphate salvage, salvage pathways of pyrimidine ribonucleotides, NF-kB signaling, NGF signaling and cell cycle control of chromosomal replication. The 9 kinase genes validated to be over-expressed in metastatic ccRCC may represent currently unrecognized but potentially actionable therapeutic targets that warrant functional validation.


Assuntos
Carcinoma de Células Renais/genética , Perfilação da Expressão Gênica/métodos , Neoplasias Renais/genética , Proteínas Quinases/genética , Análise de Sequência de RNA/métodos , Adulto , Idoso , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Transdução de Sinais , Regulação para Cima
17.
Eur Urol Focus ; 2016 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-28753783

RESUMO

In men with advanced penile squamous cell carcinoma receiving first-line chemotherapy, visceral metastases (VM) and Eastern Cooperative Oncology Group performance status ≥1 are poor prognostic factors for overall survival (OS). We hypothesized that tumor gene expression profiling may enhance prognostic stratification and identify potential therapeutic targets. In this retrospective study, RNA extracted from macrodissected tumors underwent profiling for the expression of 738 genes using NanoString. Univariate and multivariate analyses assessed the association of genes, VM, and performance status with OS. Tumors were available from 25 men who received first-line cisplatin-based chemotherapy. In univariate analysis, upregulated MAML2 (p=0.004), KITLG (p≤0.0001), and JAK1 (p=0.029) genes were associated with poor OS, and upregulated FANCA was associated with better OS (p=0.024). In stepwise multivariate analyses, VM (hazard ratio=12.75, p=0.0001) and MAML2 (hazard ratio=10.411, p=0.003) were associated with poor OS. The presence of none, one, and both of these poor risk factors was associated with significantly different median OS of 18.4 mo, 7.2 mo, and 2.1 mo, respectively. Unsupervised clustering demonstrated two major molecular subtypes with trend for different survivals (p=0.052). Validation of results is necessary. PATIENT SUMMARY: The expression of the MAML2 gene in penile cancers from men receiving first-line cisplatin-based chemotherapy predicted overall survival independent of clinical factors.

18.
Eur Urol ; 69(4): 624-633, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26497923

RESUMO

CONTEXT: Gemcitabine/platinum chemotherapy is the most widely used first-line regimen for metastatic urothelial carcinoma, and the potential improvement of adding taxanes needs to be clarified. OBJECTIVE: To study the survival impact of taxane plus gemcitabine/platinum compared with gemcitabine/platinum alone as upfront therapy. EVIDENCE ACQUISITION: Literature was searched for studies including gemcitabine/platinum ± taxanes (paclitaxel or docetaxel only). We pooled trial level data including the median, proportions, and confidence intervals on response-rate, progression-free survival, overall survival (OS), and side effects. Univariable and multivariable regression models evaluated the prognostic role of addition of taxanes after adjusting for platinum type, performance status 2, and the presence of visceral metastases. Data were weighted by the logarithm of the trial sample size. EVIDENCE SYNTHESIS: Thirty-five arms of trials including 2,365 patients were selected (seven with taxanes [n=617], and 28 arms without taxanes [n=1,748]). Median OS was univariably significantly different (p=0.019) between trials with and without taxanes. Across trials, the median 'median OS' amongst trials containing taxanes was 15.5 mo, compared with 12.5 mo in trials which did not. Multivariably, visceral disease and performance status were significantly associated with OS, and the addition of taxanes trended toward significantly better OS (p=0.056) and increase in grade ≥ 3 neurotoxicity (p=0.051), regardless of specific platinum agent used. CONCLUSIONS: In this meta-analysis, adding taxanes to gemcitabine and platinum showed a trend for improved OS and higher grade ≥ 3 neurotoxicity. Improvements in patient selection and the evaluation of a more potent and tolerable tubulin inhibitor in combination with gemcitabine/platinum in a well-powered trial are the critical next steps. PATIENT SUMMARY: In this report, a trend for improved overall survival and worse neurotoxicity was observed for adding a taxane to first-line gemcitabine/platinum chemotherapy for metastatic urothelial carcinoma. More effective taxanes should be investigated further in urothelial carcinoma in combination with gemcitabine/platinum.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/tratamento farmacológico , Desoxicitidina/análogos & derivados , Compostos de Platina/administração & dosagem , Taxoides/administração & dosagem , Neoplasias Urológicas/tratamento farmacológico , Urotélio/efeitos dos fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma/mortalidade , Carcinoma/secundário , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Progressão da Doença , Intervalo Livre de Doença , Humanos , Análise Multivariada , Compostos de Platina/efeitos adversos , Fatores de Risco , Taxoides/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Neoplasias Urológicas/mortalidade , Neoplasias Urológicas/patologia , Urotélio/patologia
19.
Front Pharmacol ; 7: 487, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28066240

RESUMO

Introduction and objectives: Metastatic penile squamous cell carcinoma (PSCC) is associated with dismal outcomes with median overall survival (OS) of 6-12 months in the first-line and <6 months in the salvage setting. Given the rarity of this disease, randomized trials are difficult. Prognostic risk models may assist in rational drug development by comparing observed outcomes in nonrandomized phase II studies and retrospective data vs. predicted outcomes based on baseline prognostic factors in the context of historically used agents. In this retrospective study, we constructed a prognostic model in the salvage setting of PSCC patients receiving second or later line systemic treatment, and also explored differences in outcomes based on type of treatment. Materials and methods: We performed a chart review to identify patients with locally advanced unresectable or metastatic PSCC who received second or later line systemic treatment in centers from North America and Europe. The primary outcome was OS from initiation of treatment, with secondary outcomes being progression-free survival (PFS) and response rate (RR). OS was estimated using the Kaplan-Meier method. Cox proportional hazards regression was used to identify prognostic factors for outcomes using univariable and multivariable models. Results: Sixty-five patients were eligible. Seventeen of 63 evaluable patients had a response (27.0%, 95% confidence interval [CI] = 16.6-39.7%) and median OS and PFS were 20 (95% CI = 20-21) and 12 (95% CI = 12, 16) weeks, respectively. Visceral metastasis (VM) and hemoglobin (Hb) ≤ 10 gm/dl were consistently significant poor prognostic factors for both OS and PFS, and Hb was also prognostic for response. The 28 patients with neither risk factor had a median OS (95% CI) of 24 (20-40) weeks and 1-year (95% CI) OS of 13.7% (4.4-42.7%), while the 37 patients with 1 or 2 risk factors had median OS (95% CI) of 20 (16-20) weeks and 1-year (95% CI) OS of 6.7% (1.8-24.9%). Cetuximab-including regimens were associated with a trend for improved RR compared to other agents (Odds ratio = 5.05, 95% CI = 0.84-30.37, p = 0.077). Taxanes vs. non-taxane, and combination vs. single agent therapy was not associated with improved outcomes. The study is limited by its modest sample size. Conclusion: This is the first prognostic classification proposed for patients receiving salvage systemic therapy for advanced PSCC. The presence of VM and Hb ≤ 10 gm/dl was associated with poor OS and PFS. Cetuximab appeared to be associated with better RR. This prognostic model may assist in salvage therapy drug development for this orphan disease by improving interpretation of outcomes seen in nonrandomized data.

20.
PLoS One ; 10(9): e0139267, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26406598

RESUMO

Despite the widespread use of kinase-targeted agents in clear cell renal cell carcinoma (CC-RCC), comprehensive kinase activity evaluation (kinomic profiling) of these tumors is lacking. Thus, kinomic profiling of CC-RCC may assist in devising a classification system associated with clinical outcomes, and help identify potential therapeutic targets. Fresh frozen CC-RCC tumor lysates from 41 clinically annotated patients who had localized disease at diagnosis were kinomically profiled using the PamStation®12 high-content phospho-peptide substrate microarray system (PamGene International). Twelve of these patients also had matched normal kidneys available that were also profiled. Unsupervised hierarchical clustering and supervised comparisons based on tumor vs. normal kidney and clinical outcome (tumor recurrence) were performed and coupled with advanced network modeling and upstream kinase prediction methods. Unsupervised clustering analysis of localized CC-RCC tumors identified 3 major kinomic groups associated with inflammation (A), translation initiation (B), and immune response and cell adhesions (C) processes. Potential driver kinases implicated include PFTAIRE (PFTK1), PKG1, and SRC, which were identified in groups A, B, and C, respectively. Of the 9 patients who had tumor recurrence, only one was found in Group B. Supervised analysis showed decreased kinase activity of CDK1 and RSK1-4 substrates in those which progressed compared to others. Twelve tumors with matching normal renal tissue implicated increased PIM's and MAPKAPK's in tumors compared to adjacent normal renal tissue. As such, comprehensive kinase profiling of CC-RCC tumors could provide a functional classification strategy for patients with localized disease and identify potential therapeutic targets.


Assuntos
Carcinoma de Células Renais/genética , Perfilação da Expressão Gênica , Neoplasias Renais/genética , Proteínas Quinases/metabolismo , Carcinoma de Células Renais/patologia , Análise por Conglomerados , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Proteínas Quinases/genética , Resultado do Tratamento
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