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Academic literature on the topic 'Pbrm1'

Author: Grafiati

Published: 4 June 2021

Last updated: 8 February 2022

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Journal articles on the topic "Pbrm1"

Mota, Sara T. S., Lara Vecchi, Mariana A. P. Zóia, Fabrícia M. Oliveira, Douglas A. Alves, Bruno C. Dornelas, Stephania M. Bezerra, et al. "New Insights into the Role of Polybromo-1 in Prostate Cancer." International Journal of Molecular Sciences 20, no. 12 (June 12, 2019): 2852. http://dx.doi.org/10.3390/ijms20122852.

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The human protein Polybromo-1 (PBMR1/BAF180) is a component of the SWI/SNF chromatin-remodeling complex that has been reported to be deregulated in tumors. However, its role in prostate cancer (PCa) is largely unknown. In this study, we described the PBRM1 transcriptional levels and the protein expression/localization in tissues of PCa patients and in prostatic cell lines. Increased PBRM1 mRNA levels were found in PCa samples, when compared to benign disease, and were correlated with higher Gleason score. We also verified that only the nuclear localization of PBRM1 protein is correlated with a more aggressive disease and high Prostate-Specific Antigen (PSA) levels in tissue microarrays. Intriguing expression patterns of mRNA and protein were identified in the cell lines. Although PBRM1 protein was restricted to the nuclei, in tumor cell lines in non-neoplastic cells, it was also present in vesicular-like structures that were dispersed within the cytoplasm. We knocked-down PBRM1 in the castration-resistant PCa (CRPC) cell line PC-3 and we verified that PBRM1 promotes the expression of several markers of aggressiveness, including EpCAM, TGF-β, and N-Cadherin. Therefore, our data supported the hypothesis that PBRM1 displays a pivotal role in the promotion and maintenance of the malignant behavior of PCa, especially in CRPC.

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Dizman, Nazli, Paulo Gustavo Bergerot, Cristiane Decat Bergerot, Joann Hsu, and Sumanta K. Pal. "Duration of treatment (DOT) with targeted therapies (TT) or immunotherapy (IO) in PBRM1 mutated metastatic renal cell carcinoma (mRCC)." Journal of Clinical Oncology 37, no. 7_suppl (March 1, 2019): 622. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.622.

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622 Background: Current evidence indicates improved outcome with IO in mRCC patients (pts) with PBRM1 loss of function mutations (Miao et al., Nature, 2018). We seek to demonstrate an association between PBRM1 mutation and treatment duration with IO and TT in a retrospective cohort. Methods: Consecutive patients with mRCC who had genomic profiling in the course of routine clinical care were identified from an institutional database. GP assessments included testing either tissue or blood with 1 of the 3 CLIA certified commercial panels (Foundation Medicine, Cambridge, MA; Ashion Analytics, Phoenix, AZ; Guardant Health, Redwood City, CA). Information regarding systemic treatment was collected. Median DOT with first targeted therapy and first immunotherapy received was calculated for each patient. DOT was compared across treatment groups in PBRM1+ and PBRM1- patients. Only PBRM1 mutations with functional significance documented in COSMIC were considered. Results: Among 104 pts (72:32 M:F) with mRCC, 82 pts received TT, 35 pts received IO, and 45 pts received both. GP was performed in blood and tissue in 84 and 63 pts, respective, and 25 pts (24%) with PBRM1 mutations were identified. Among PBRM1+ pts, median DOT was 8.8 months (95% CI, 7.6-9.6) mos and 2.3 mos (95% CI, 1.7 – 2.8) mos with TT and IO, respectively (p=0.049). Among PBRM1- pts, median DOT was 5.5 mos and 2.8 mos with TT and IO, respectively (p=0.544). There were 11 PBRM1+ pts and 34 PBRM- pts who received both TT and IO. The ratio of DOT on IO to DOT on TT (DOTIO/TT) was higher in PBRM1- pts than PBRM1+ pts (0.76 versus 0.37 respectively, p=0.014). Conclusions: We failed to replicate the results from Miao et al, suggesting clinical benefit with IO in PBRM1 mutated patients. PBRM1 mutation did appear to predict benefit with TT versus IO. Although limited by sample size, the contrasting results of the current study with literature highlight the importance of clinical validation in a large and prospective setting.

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Shmakova, Alena, Mark Frost, Michael Batie, Niall S. Kenneth, and Sonia Rocha. "PBRM1 Cooperates with YTHDF2 to Control HIF-1α Protein Translation." Cells 10, no. 6 (June 8, 2021): 1425. http://dx.doi.org/10.3390/cells10061425.

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PBRM1, a component of the chromatin remodeller SWI/SNF, is often deleted or mutated in human cancers, most prominently in renal cancers. Core components of the SWI/SNF complex have been shown to be important for the cellular response to hypoxia. Here, we investigated how PBRM1 controls HIF-1α activity. We found that PBRM1 is required for HIF-1α transcriptional activity and protein levels. Mechanistically, PBRM1 is important for HIF-1α mRNA translation, as absence of PBRM1 results in reduced actively translating HIF-1α mRNA. Interestingly, we found that PBRM1, but not BRG1, interacts with the m6A reader protein YTHDF2. HIF-1α mRNA is m6A-modified, bound by PBRM1 and YTHDF2. PBRM1 is necessary for YTHDF2 binding to HIF-1α mRNA and reduction of YTHDF2 results in reduced HIF-1α protein expression in cells. Our results identify a SWI/SNF-independent function for PBRM1, interacting with HIF-1α mRNA and the epitranscriptome machinery. Furthermore, our results suggest that the epitranscriptome-associated proteins play a role in the control of hypoxia signalling pathways.

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Fay, Andre Poisl, Guillermo de Velasco, Kathryn P. Gray, Thai Huu Ho, Jiaxi Song, Payal Kapur, Laurence Albiges, et al. "The impact of PBRM1 and BAP1 expression on outcomes of patients with metastatic renal cell carcinoma (mRCC) treated with VEGF-targeted therapy (TT)." Journal of Clinical Oncology 34, no. 2_suppl (January 10, 2016): 616. http://dx.doi.org/10.1200/jco.2016.34.2_suppl.616.

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616 Background: Polybromo-1 (PBRM1) and BRCA1 associated protein-1 (BAP1) are genes commonly mutated in clear cell RCC (ccRCC) and have been associated with clinical outcome. This work aims to evaluate the impact of PBRM1 and BAP1 expression by IHC in mRCC patients treated with VEGF-TT. Methods: PBRM1 and BAP1 expression was evaluated by IHC in a TMA including 146 mRCC patients. PBRM1 and BAP1 IHC scores were dichotomized as a binary variable: negative (-) or positive (+) (weak positivity was excluded). The associations of PBRM1 or BAP1 expression with baseline clinico-pathological characteristics were evaluated, as well as with overall survival (OS) and time to treatment failure (TTF) usingCox proportional hazards models. Results: Out of 146 patients, 116 and 109 samples had available results for PBRM1 and BAP1 staining, respectively. Overall, 90% (n = 131) patients had ccRCC. 70/116 samples (60%) were PBRM1- and 26/109 patients (24%) were BAP1-. Only 12% (n = 13) of patients had simultaneous negative PBRM1 and BAP1. While there was no association between PBRM1 expression status and clinical factors, BAP1- samples were associated with poor IMDC prognostic risk score (p = 0.004) and higher Fuhrman grade (p = 0.012). PBRM1+ patients showed a trend towards an increased risk of death and a shorter TTF compared to PBRM1- patients (OS: HR = 1.38, 95%CI: 0.92-2.07, p = 0.1; TTF: HR = 1.39, 95%CI: 0.94-2.06, p = 0.1). BAP1 expression was not independently associated with OS or TTF. Conclusions: Loss of PBRM1, but not BAP1 expression showed a trend towards longer TTF and OS in mRCC patients treated with VEGF-TT.

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Pal, Sumanta K., Russell Madison, Jon Chung, Neeraj Agarwal, Paulo Gustavo Bergerot, Dominick Bosse, Ethan Sokol, et al. "Comparison of tumor mutational burden (TMB) in PBRM1/BAP1-based subsets of advanced renal cell carcinoma (aRCC)." Journal of Clinical Oncology 36, no. 6_suppl (February 20, 2018): 634. http://dx.doi.org/10.1200/jco.2018.36.6_suppl.634.

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634 Background: Using IHC, Joseph et al (J Urol 2016) propose that 40.1%, 48.6%, 8.7% and 1.8% of patients (pts) can be characterized as PBRM1+BAP1+, PRBM1-BAP1+, PBRM1+BAP1- and PBRM1-BAP1-, respectively. We sought to confirm consistency of the frequency of genomic alterations (GAs) and IHC data and to compare TMB across subsets. Methods: DNA was extracted from 40 microns of FFPE sections from pts with aRCC. Comprehensive genomic profiling (CGP) was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 688X for up to 315 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. TMB was determined on 1.2 million Mb of sequenced DNA; results are reported in subsets segregated by presence or absence of PBRM1 and BAP1 alteration. Results: 648 consecutive pts (459:189 M:F) with clear cell RCC (ccRCC) were assessed with a median age of 58, and 368 consecutive pts (254:114 M:F) with non-clear cell RCC (nccRCC) were assessed with a median age of 57. Mutations in BAP1 and PBRM1 were found more frequently in ccRCC vs nccRCC (P < 0.05 for both). In pts with ccRCC, average TMB was highest in pts with co-occurring PBRM1 and BAP1 GAs (4.87 muts/Mb), and lowest in pts lacking both GAs (2.77 muts/Mb) (P < 0.05). TMB was similar across PBRM1/BAP1-based subsets amongst pts with nccRCC. Conclusions: As anticipated, the frequency of PBRM1/BAP1-mutated subsets by CGP is inversely related to the frequency of subsets with PBRM1/BAP1 loss by IHC from previous reports. In addition to these confirmatory findings, this large series identifies that pts with dual PBRM1/ BAP1 GAs (associated with the worst prognosis) had the highest TMB. [Table: see text]

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Williams, E., P. Brastianos, S. Santagata, D. Cahill, S. Ramkissoon, and T. Juratli. "P04.09 Frequent inactivating mutations of PBRM1 in meningioma with papillary features." Neuro-Oncology 23, Supplement_2 (September 1, 2021): ii20. http://dx.doi.org/10.1093/neuonc/noab180.066.

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Abstract BACKGROUND Papillary meningiomas (PM) are rare WHO grade III tumors that are associated with frequent recurrences and metastatic disease in spite of surgery and radiation. Due to their low incidence and scarcity of tumor tissues available for genomic analyses, the genetic alterations associated with PM remain unclear. MATERIAL AND METHODS We mined data collected as part of our clinical comprehensive genomic profiling (CGP) initiative which has to date analyzed 8 PM (>50% papillary morphology) and 22 meningiomas with focal papillary features (10–50%) amongst over 500 additional meningiomas of other subtypes. The samples were analyzed in a CAP/CLIA-accredited laboratory (Foundation Medicine, Cambridge, MA). GCP was performed on hybridization-captured, adaptor ligation-based libraries to a mean coverage depth of >650x for 236 or 315 genes plus the introns from 19 or 28 genes frequently involved in cancer. RESULTS In our cohort of 8 PMs, we identified three cases with inactivation of PBRM1; two cases with a truncating mutation in PBRM1 and one with homozygous deletion of PBRM1. Of the 22 meningiomas with only focal papillary features, 8 cases were PBRM1-mutant. Thus, 11 of 30 cases (36.7%) with at least focal (>10%) papillary morphology had inactivation of PBRM1.In the entire cohort of 562 meningiomas, we identified five additional cases with inactivating alterations in PBRM1 that did not display overt papillary morphology in the H&E sections available for analysis. Thus, 11 of 16 PBRM1-mutant cases (69%) occurred in meningioma with papillary histologic features as opposed to 19 of 546 wild-type cases (3.5%), supporting a significant association between papillary features and PBRM1 mutation (p<0.0001). The majority of PBRM1-mutant meningiomas occurred in female patients (n=10/16, 62.5%), and median age was 51 years. Most cases were located supratentorially (n=10). CONCLUSION We identified the tumor suppressor gene PBRM1 as a recurrently altered gene in meningiomas with papillary histomorphology. Further investigational studies are needed to assess outcomes of PBRM1-mutant meningioma and to determine whether mutation is an independent negative prognostic biomarker.

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Joseph, Richard Wayne, Payal Kapur, Daniel Serie, Jeanette Eckel-Passow, Thai Huu Ho, James Brugarolas, and Alexander S. Parker. "Loss of BAP1 and PBRM1 protein expression and its association with clear cell renal cell carcinoma-specific survival." Journal of Clinical Oncology 32, no. 4_suppl (February 1, 2014): 414. http://dx.doi.org/10.1200/jco.2014.32.4_suppl.414.

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414 Background: While mutations in PBRM1 (~40%) and BAP1(~10%) are associated with clinical outcomes and pathologic features in clear cell renal cell carcinoma (ccRCC), the impact of protein expression of these genes remains unknown. Herein, we quantify PBRM1/BAP1 protein expression in a large cohort of patients with localized ccRCC and associate expression with cancer-specific survival (CSS) and pathologic features. Methods: We utilized the Mayo Clinic Renal Registry and identified 1,416 patients who underwent nephrectomy to treat clinically localized ccRCC between 1/3/1990 and 4/14/2009. We used immunohistochemistry (IHC) to detect PBRM1/BAP1 expression, and a central pathologist blinded to the outcomes scored tumors as either positive or negative. Tumors with heterogeneous or equivocal staining were excluded from this analysis. We generated Cox proportional hazard regression models for associations with ccRCC-SS, and we employed Mann-Whitney U tests for associations with pathologic features. Results: Of the 1,416 samples, 1,232 (87%) were PBRM1/BAP1 positive or negative, 163 (11%) had heterogeneous staining, and 21 (1%) could not be assessed. The distribution and association of PBRM1/BAP1 phenotypes with clinical outcomes are listed in the table below. PBRM1+/BAP1+ tumors have the best CSS, and PBRM1-/BAP1- have the worst. In addition, PBRM1/BAP1 expression strongly associated with the tumor size, stage, grade, and tumor necrosis (p<0.0001). Conclusions: This study is the first and largest to quantify PRBM1/BAP1 protein expression in ccRCC tumors. We were able to quantify PBRM1/BAP1 through IHC in the vast majority of tumors (87%), and PRBM1/BAP1 expression strongly associates with both CSS and pathologic tumor characteristics. Our data confirms our previous findings of the importance of PRBM1/BAP1 in the molecular pathogenesis of ccRCC. [Table: see text]

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Zimmer, Kai, Florian Kocher, Gerold Untergasser, Alberto Puccini, Joanne Xiu, Dominik Wolf, Gilbert Spizzo, et al. "Identification and prognostic impact of PBRM1 mutations in biliary tract cancers: Results of a comprehensive molecular profiling study." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 4022. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.4022.

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4022 Background: The prognosis of biliary tract cancers (BTC) remains dismal and novel treatment strategies are needed to improve survival. Polybromo-1 ( PBRM1) is a subunit of the PBF chromatin-remodeling complex and preclinical studies suggest induction of synthetic lethality by PARP inhibitors in PBRM1-mutated cancers. Therefore, we aimed to describe the molecular landscape in BTC harboring PBRM1 mutations. Methods: 1,848 BTC samples were included in this study. Specimens were analyzed using NextGen DNA sequencing (NextSeq, 592 gene panel or NovaSeq, whole-exome sequencing), whole-transcriptome RNA sequencing (NovaSeq) and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). Pathway gene enrichment analyses were done using GSEA (Subramaniam 2015, PNAS). Immune cell fraction was calculated by QuantiSeq (Finotello 2019, Genome Medicine). Survival was calculated from time of tissue collection to last contact using Kaplan-Meier estimates. Results: PBRM1 mutations were identified in 8.1% (n = 150) of BTC tumors and were more prevalent in intrahepatic BTC (9.9%) than in gallbladder cancer (6%, p = 0.0141) and in extrahepatic BTC (4.5%, p = 0.008). In PBRM1-mutated tumors, we found a higher rate of MSI-H/dMMR (8.7% vs. 2.1%, p < 0.0001) and a higher median TMB (4 vs. 3 mt/MB, p < 0.0001). When compared to PBRM1-wildtype cancers higher rates of co-mutations in chromatin-remodeling genes (e.g. ARID1A, 31% vs. 16% , p < 0.0001) and DNA damage repair pathway (e.g. ATRX, 4.4% vs. 0.3%, p < 0.0001) were detected. Within PBRM1-mutated tumors, a significant higher frequency of infiltrating M1 macrophages was observed (p < 0.0001). Gene set enrichment analysis revealed that genes associated with tumor inflammation (e.g. HLA-DRA, HLA-DRB1, IFNGR1) were enriched in PBRM1-mutated tumors (NES = 2.02, FDR = 1.3%, p < 0.0001). Overall survival analysis showed that PBRM1 mutations were associated with a favorable outcome (HR 1.502, 95% CI [1.013-2.227], p = 0.041). This relationship was also present in MSS subgroup (HR: 1.667, [1.026-2.71], p = 0.037). Conclusions: This is the largest and most extensive molecular profiling study focusing on PBRM1-mutated BTC. Co-mutations in chromatin-remodelling and DNA damage repair genes might set the stage for clinical testing of PARP inhibitors in PBRM1-mutated BTC. Moreover, a distinct tumor microenvironment characterized by high M1 macrophages infiltration and an enrichment of inflammatory genes suggest a potential benefit of immunotherapy.

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Hakimi, A. Ari, Yasser Ged, Jessica Flynn, Douglas R. Hoen, Renzo G. Di Natale, Kyle A. Blum, Vladimir Makarov, et al. "The impact of PBRM1 mutations on overall survival in greater than 2,100 patients treated with immune checkpoint blockade (ICB)." Journal of Clinical Oncology 37, no. 7_suppl (March 1, 2019): 666. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.666.

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666 Background: PBRM1 is the second most commonly mutated gene in clear cell renal cell carcinoma (ccRCC). We have previously shown favorable outcomes in PBRM1-mutated ccRCC tumors treated with vascular endothelial growth factor (VEGF) inhibitors. Recent data suggested PBRM1 mutations may sensitize ccRCC and non RCC malignancies to ICB therapy. We queried the impact of PBRM1 loss on overall survival (OS) across 2,152 patients treated with ICB. Methods: PBRM1 mutations were assessed in metastatic ccRCC patients who received first line (n = 82) or second line (n = 61) ICB or ICB/VEGF combinations. Additionally, 41 cohorts of non-RCC malignancies treated with ICB and combination (n = 2,009) were analyzed. Mutations were assessed by next generation targeted sequencing using archival tissue. Association of mutation status and overall survival (OS) was tested by multivariate Cox regression analysis (MVA) and adjusted for tumor mutation burden (TMB), copy number alterations (CNA), loss of function(LOF) mutations (non RCC cohort) and IMDC risk (for ccRCC patients). Results: PBRM1 mutations were not associated with improved OS in ICB the entire ccRCC cohort (HR 1.37; CI 0.79-2.4; p = 0.265), the first line (p = 0.624) or second line setting (p = 0.39) or as combination with VEGF inhibitors (p = 0.2). Several RCC subgroups were investigated (see Table at bottom). In the non-RCC cohorts (n = 2,009) PBRM1 mutations were not significantly associated with OS on univariate analysis (HR = 0.73, p = 0.22 for LOF and HR = 0.84,p = 0.34 for non LOF), and remained insignificant after adjusting for TMB, total CNA, and drug class (CTLA4, PD-1/PDL-1 and combinations) (HR = 1.07, p = 0.78 for LOF and HR = 1.08,p = 0.67 for non LOF). Conclusions: Neither in ccRCC nor in the pan-cancer cohort did PBRM1 mutations appear to be associated with improved overall survival with ICB therapy.[Table: see text]

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Brugarolas, James, Payal Kapur, Samuel Pena-Llopis, Alana Christie, and Xian-Jin Xie. "Toward a molecular genetic classification of clear cell renal cell carcinoma." Journal of Clinical Oncology 31, no. 6_suppl (February 20, 2013): 341. http://dx.doi.org/10.1200/jco.2013.31.6_suppl.341.

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341 Background: Clear cell renal cell carcinoma (ccRCC) displays a variety of clinical behaviors. However, the molecular underpinnings are unknown. We discovered that BAP1 is mutated in approximately 15% of ccRCC and that BAP1 and PBRM1mutations are largely mutually exclusive. Herein, we investigate the clinicopathological significance of these molecular subtypes. Methods: Tumors from 145 patients with primary ccRCC were sequenced for PBRM1 and BAP1. Tumors were classified into BAP1-mutated and those exclusively mutated for PBRM1. Tumors were evaluated for pathologic features, gene expression and associated outcomes. A second independent cohort (n=327) from The Cancer Genome Atlas (TCGA) was used for validation. Results: When compared to PBRM1-mutant tumors, BAP1-mutant tumors were associated with aggressive pathological features including high Fuhrman grade and tumor necrosis. BAP1-mutant and PBRM1-mutant tumors exhibited distinct gene expression signatures. The median overall survival (OS) was shorter for patients with BAP1-mutant tumors (4.6 years; 95% CI, 2.1-7.2), than for patients with PBRM1-mutant tumors (10.6 years; 95% CI, 9.8-11.5), corresponding to a hazard ratio (HR) of 2.7 (95% CI, 0.99-7.6, p = 0.044). A similar HR was observed in the independent dataset from the TCGA (2.8; 95% CI, 1.4-5.9; p = 0.004). The BAP1-mutant group could be further subdivided into tumors with mutations exclusively in BAP1 and those with mutations in both BAP1 and PBRM1. Double mutant tumors constituted a minority (n = 4; in TCGA), and were associated with the shortest OS (HR, 10; 95% CI, 3.2-33.6). Conclusions: Our findings reveal novel biological subgroups of ccRCC with distinct clinical outcomes, a high-risk BAP1-mutant group and a favorable PBRM1-mutant group. These data establish the basis for a molecular subclassification of ccRCC that could influence treatment decisions in the future.

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Dissertations / Theses on the topic "Pbrm1"

Shmakova, Alena. "Role of PBRM1 in regulation of the HIF pathway." Thesis, University of Dundee, 2016. https://discovery.dundee.ac.uk/en/studentTheses/e187ce7a-1286-46bf-ae09-297ca6f623b2.

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Hypoxia Inducible Factors are a family of transcription factors mediating the transcriptional response to hypoxia. They are heterodimers consisting of an oxygen-regulated α subunit and an oxygen-independent β subunit. In normoxia HIFα is quickly degraded by a VHL-mediated mechanism whereas hypoxia stabilizes this subunit making it available to form an active complex and induce transcription of its target genes. Recently, it was shown that the SWI/SNF chromatin remodeling complex plays an important role in HIF transcriptional responses. SWI/SNF is a large multiprotein complex composed of at least 15 subunits. PBRM1 is a distinctive subunit of the PBAF subcomplex of SWI/SNF that was recently found to be mutated in different cancer types such as pancreatic, breast, and renal. Interestingly, PBRM1 and VHL are the most frequently mutated genes in clear cell Renal Cell Carcinoma (ccRCC). Mutations or loss of VHL leads to upregulation of both HIF1α and HIF2α. However, recent studies indicate that HIF1α and HIF2α play opposing roles in renal cancer progression: HIF1α is a tumour suppressor whereas HIF2α acts an oncogene. Here, it is shown that PBRM1 is able to selectively regulate the expression of HIF1α in a BRG1-independent manner. PBRM1 is important for recognition of HIF1α mRNA by YTHDF2 and able to interact with mRNA suggesting a link between this chromatin remodeling complex and mRNA processing. Additionally, PBRM1 contributes to the hypoxia induced expression of HK2 and PHD2 genes, possibly by interacting with HIF1 at HRE sites in the promoters of these genes.

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Högner, Anica [Verfasser]. "Die Rolle der Tumorsuppressorgene PBRM1 und VHL in der Tumorigenese des klarzelligen Nierenzellkarzinoms / Anica Högner." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2018. http://d-nb.info/1176637460/34.

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Morel, Daphné. "Identifying Synthetic Lethal and Selective Approaches to Target PBRM1-Deficiency in Clear Cell Renal Cell Carcinoma PBRM1 Deficiency in Cancer is Synthetic Lethal with DNA Repair Inhibitors Exploiting Epigenetic Vulnerabilities in Solid Tumors: Novel Therapeutic Opportunities in the Treatment of SWI/SNF-Defective Cancers Combining Epigenetic Drugs with other Therapies for Solid Tumours — Past Lessons and Future Promise Targeting Chromatin Defects in Selected Solid Tumors Based on Oncogene Addiction, Synthetic Lethality and Epigenetic Antagonism." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL017.

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L’inactivation de polybromo-1 (PBRM1) est un évènement fréquent dans de nombreux cancers. En particulier, les carcinomes rénaux à cellules claires présentent une déficience en PBRM1 dans 40 à 50% des cas. A ce jour, il n’existe pas d’approche de médecine précision connue capable de cibler spécifiquement les cellules tumorales déficientes en PBRM1.Pour identifier des cibles de létalité synthétique associées à la perte de PBRM1, nous avons (i) réalisé un criblage pharmacologique à haut débit évaluant la sensibilité à 167 molécules dans un modèle cellulaire isogénique pour PBRM1, et (ii) étudié l’impact transcriptomique et protéomique de la perte de PBRM1 dans ce même modèle.Nous avons ensuite caractérisé les mécanismes sous-jacents à la relation de létalité synthétique découverte.Nous avons identifié et validé une relation de létalité synthétique existante entre la perte tumorale de PBRM1 et l’inhibition pharmacologique de PARP, pouvant être potentialisée par l’ajout d’un inhibiteur d’ATR.Cette relation de létalité synthétique était caractérisée par un niveau basal élevé de stress cellulaire chez les cellules déficientes en PBRM1, associant anomalies mitotiques, stress transcriptionnel et stress réplicatif – tous ces phénomènes étant exacerbés à l’ajout d’inhibiteurs de PARP, jusqu’à dépasser les capacités cellulaires à maintenir un phénotype compatible avec la survie.Ces observations apportent la preuve de concept préclinique que les inhibiteurs de PARP sont de potentiels candidats thérapeutiques pour cibler spécifiquement les tumeurs déficientes en PBRM1
Polybromo-1 (PBRM1) inactivation occurs in multiple malignancies and is of particular importance in clear cell renal cell carcinomas (ccRCC), as it drives 40 to 50% of cases. Currently, no precision-medicine approach uses PBRM1 deficiency to specifically target tumour cells. To uncover novel synthetic lethal approaches to treat PBRM1-defective cancers, we performed (i) a high-throughput pharmacological screening, evaluating the sensitivity to 167 small molecules in a PBRM1-isogenic cellular model, and the (ii) systematic mapping of the whole transcriptomic and proteomic profiles associated with PBRM1 loss-of-function within this model. We further investigated the mechanism underlying this synthetic lethal relationship.We identified and validated synthetic lethal effects between PBRM1 loss and both PARP and ATR inhibition. Combinatorial use of PARP with ATR inhibitors exerted additive cytotoxic effects in PBRM1-defective tumor cells. These synthetic lethal relationships were characterized by a pre-existing replication stress in PBRM1-deficient cells associated with mitosis and DNA damage repair abnormalities, which were exacerbated upon PARP inhibition selectively in PBRM1-defective cells.These data provide the preclinical basis for evaluating PARP inhibitors as a monotherapy or in combination in patients with PBRM1-deficient ccRCC

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Trottier, Alexandre. "Étude de l'action du PBRM, un inhibiteur de la 17β-hydroxystéroïde déshydrogénase (17β--HSD) type 1 : ...qui mena à la découverte fortuite d'un 1er activateur de la 17β-HSD type 12." Master's thesis, Université Laval, 2014. http://hdl.handle.net/20.500.11794/25503.

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Les 17β-hydroxystéroïdes déshydrogénases (17β-HSD) sont un groupe de 15 enzymes connues avant tout pour leur rôle dans le métabolisme des hormones sexuelles. La 17β-HSD1 est responsable de la toute dernière étape dans la fabrication des estrogènes actifs. Cela en fait une cible intéressante pour traiter l’endométriose et le cancer du sein qui sont stimulées par ces hormones. Le dérivé stéroïdien PBRM, conçu dans notre laboratoire, est l’une des rares molécules ayant démontré une inhibition forte et spécifique de la 17β-HSD1. Lors des présents travaux, l’effet de l’inhibiteur s’est avéré irréversible, sélectif et durable tout en présentant un profil intéressant chez la souris. Durant ce processus, plusieurs composés n’ayant pas les qualités requises ont été mis de côté. Parmi eux, l’un s’est avéré être un activateur de la 17β-HSD12, une enzyme essentielle dans l’élongation des acides gras. Il s’agit là du premier activateur rapporté pour la famille des 17β-HSD.
17β-Hydroxysteroid dehydrogenases (17β-HSD) are a group of 15 enzymes known firstly for their involvement in sexual hornomes metabolism. 17β-HSD1 is responsible of the last step in the biosynthesis of potent estrogens. It is thus an interesting target to treat diseases stimulated by those hormones such as endometriosis and breast cancer. PBRM, a steroidal inhibitor developed in our laboratory, is one of the few molecules that shown a strong and specific inhibition of 17β-HSD1. The present works showed that the inhibitory effect is irreversible, selective and long-lasting while showing an interesting profil in mice. During that process, many other compounds were tested but didn’t have the required qualities. Among them, one seemed to stimulate the activity of 17β-HSD12, an essential enzyme for fatty acids elongation also involved in estrogen metabolism. It is the first reported activator for a member of 17β-HSD family.

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Schoenfeld, David Aaron. "Characterizing the Mechanism of Tumor Suppression by PBRM1 in Clear Cell Renal Cell Carcinoma." Thesis, 2015. https://doi.org/10.7916/D8B56JJX.

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In this study, we investigated the mechanisms by which PBRM1 functions as a tumor suppressor in clear cell renal cell carcinoma. PBRM1, also known as BAF180 or Polybromo, is a member of the PBAF SWI/SNF chromatin remodeling complex. Cancer sequencing studies have revealed that SWI/SNF components are widely mutated in cancer. PBRM1 is recurrently mutated in various human malignancies, but it has a particularly high mutation rate in clear cell renal cell carcinoma: ~40% of clear cell renal cell carcinomas have a PBRM1 mutation, making it the second most highly mutated gene in clear cell renal cell carcinoma behind VHL. Although many recent studies have looked at how other SWI/SNF components function in cancer control, relatively little is known about the tumor suppressive mechanisms of PBRM1 in clear cell renal cell carcinoma. To investigate PBRM1 function, we manipulated its expression in clear cell renal cell carcinoma cell lines. In cell lines with intact PBRM1, we stably knocked down its expression using shRNA. In a cell line with mutant PBRM1, we stably restored expression of the wild-type protein. We found that PBRM1 deficiency significantly enhanced the growth properties of cells, but only when the cells were grown under stressful conditions, such as reduced serum or a 3-D culture environment. To investigate genes and pathways influenced by PBRM1 that may confer this growth advantage, we compared gene expression differences in the clear cell renal cell carcinoma cell lines and murine embryonic fibroblasts with or without PBRM1. We found that PBRM1 regulated numerous cancer-related genes and pathways. One gene, ALDH1A1, was consistently upregulated with PBRM1 deficiency across our cell lines. Further expression analysis using two different clear cell renal cell carcinoma primary tumor datasets revealed that PBRM1 mutation in primary tumors was also associated with higher ALDH1A1 levels. ALDH1A1, or aldehyde dehydrogenase 1, is part of the retinoic acid metabolic pathway and irreversibly converts retinaldehyde to retinoic acid. It functions in hematopoietic stem cell development, white versus brown fat programming, and insulin signaling. Numerous studies have also identified ALDH1A1 as a marker of tumor-initiating cells, also known as cancer stem cells. Not much is known about the regulation of ALDH1A1 expression in cancer, and it has not previously been linked to PBRM1 or SWI/SNF. We confirmed that stable knockdown of PBRM1 in clear cell renal cell carcinoma cell lines resulted in higher ALDH1A1 mRNA and protein expression, and also higher ALDH1-class enzyme activity. Alternatively, re-expression of wild-type PBRM1, but not cancer-associated mutant PBRM1, lowered ALDH1A1 expression and activity in the PBRM1-mutant line. Additionally, inhibiting ALDH1A1 or knocking it down in the context of PBRM1 deficiency reduced anchorage-independent growth, while over-expressing ALDH1A1 in the PBRM1-normal setting increased tumorsphere-forming capacity. These results suggest that ALDH1A1 is not only a marker of tumor-initiating cells, but can also increase the tumorigenic potential of cells. Based on our gene expression analysis, we additionally explored PBRM1 regulation of the EGFR and IFN pathways. PBRM1 decreased total EGFR protein levels and dampened downstream signaling. These changes had functional consequences, as PBRM1 deficiency led to faster growth in response to EGF stimulation. However, it did not create a setting of oncogenic addiction, as PBRM1 deficient cells were also more resistant to EGFR inhibition. Alternatively, PBRM1 deficiency reduced basal and IFNα-induced levels of IFI27, a pro-apoptotic interferon response gene, and made cells more resistant to growth inhibition by IFNα. PBRM1 mutations in cancer would thus be expected to have wide-ranging effects on a cell, and the targeting of any one specific downstream pathway might have limited efficacy. Finally, we investigated the molecular mechanisms of how PBRM1 deficiency could alter transcription, keeping in mind that PBRM1 is one subunit of the larger PBAF complex. In our clear cell renal cell carcinoma cell lines, we found that mRNA and protein levels of another PBAF-specific subunit, ARID2, increased with PBRM1 deficiency. PBRM1 mutation in primary tumors was also associated with significantly higher ARID2 expression. Immunoprecipitation and glycerol gradient fractionation experiments suggested that more ARID2 may associate with the SWI/SNF components BRG1 and SNF5 after PBRM1 knockdown. ARID2 ChIP-seq analysis revealed that this remnant PBAF-like complex was bound to fewer locations in the genome, and its binding locations were broadly redistributed. Both gained and lost ARID2 binding were associated with differential gene expression, of both upregulated and downregulated genes, indicating that the genomic context influences whether PBAF-binding is activating or repressive. Interestingly, we also found that ARID2 was required for some of the pro-tumorigenic changes associated with PBRM1 deficiency, such as upregulation of ALDH1A1 and EGFR levels, but not others, such as decreased IFI27 levels, implying alternative modes of transcriptional regulation. In total, this study implicates PBRM1 in the regulation of numerous cancer-related genes and pathways in clear cell renal cell carcinoma. PBRM1 mutation would alter the genomic binding of a residual PBAF-like complex containing ARID2, leading to transcriptional changes that promote tumor formation and growth. A better understanding of this oncogenic mechanism may reveal novel therapeutic opportunities.

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Books on the topic "Pbrm1"

Eisen, Tim. The patient with renal cell cancer. Edited by Giuseppe Remuzzi. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0172.

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Renal cancer is the commonest malignancy of the kidney and worldwide, accounts for between 2% and 3% of the total cancer burden. The mainstay of curative treatment remains surgery. There have been significant advances in surgical technique, the most important ones being nephron-sparing surgery and laparoscopic nephrectomy. The medical treatment of advanced renal cell cancer has only improved markedly in the last decade with the development of antiangiogenic tyrosine-kinase inhibitors, inhibitors of mammalian target of rapamycin, and a diminished role for immunotherapy.Tyrosine-kinase inhibitor therapy results in reduction of tumour volume in around three-quarters of patients and doubles progression-free survival, but treatment is not curative. The management of side effects in patients on maintenance tyrosine-kinase inhibitors has improved in the last 3 years, although still presents difficulties which have to be actively considered.The molecular biology of renal cell carcinoma is better understood than for the majority of solid tumours. The commonest form of renal cancer, clear-cell carcinoma of the kidney, is strongly associated with mutations in the von Hippel–Lindau gene and more recently with chromatin-remodelling genes such as PBRM1. These genetic abnormalities lead to a loss of control of angiogenesis and uncontrolled proliferation of tumour cells. There is a very wide spectrum of tumour behaviour from the extremely indolent to the terribly aggressive. It is not currently known what accounts for this disparity in tumour behaviour.A number of outstanding questions are being addressed in scientific and clinical studies such as a clearer understanding of prognostic and predictive molecular biomarkers, the role of adjuvant therapy, the role of surgery in the presence of metastatic disease, how best to use our existing agents, and investigation of novel targets and therapeutic agents, especially novel immunotherapies.

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Book chapters on the topic "Pbrm1"

Lee, Chung-Han, Can G. Pham, and James J. Hsieh. "PBRM1: A Critical Subunit of the SWI/SNF Chromatin Remodeling Complex." In Renal Cell Carcinoma, 111–51. New York, NY: Springer New York, 2014. http://dx.doi.org/10.1007/978-1-4939-1622-1_5.

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Sarkar, Abhijit, Madhumonti Saha, and Vijay Singh Meena. "Plant Beneficial Rhizospheric Microbes (PBRMs): Prospects for Increasing Productivity and Sustaining the Resilience of Soil Fertility." In Agriculturally Important Microbes for Sustainable Agriculture, 3–29. Singapore: Springer Singapore, 2017. http://dx.doi.org/10.1007/978-981-10-5589-8_1.

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Conference papers on the topic "Pbrm1"

Liu, Xian-De, Wen Kong, Anh Hoang, Xuesong Zhang, Lijun Zhou, Patrick G. Pilie, Sevinj Isgandrova, Margie M. Moczygemba, and Eric Jonasch. "Abstract B48: PBRM1 loss promotes resistance to immunotherapy in RCC." In Abstracts: AACR Special Conference on Tumor Immunology and Immunotherapy; November 27-30, 2018; Miami Beach, FL. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/2326-6074.tumimm18-b48.

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Chowdhury, Basudev. "Abstract 3362: PBRM1 regulates the transcription of cell adhesion genes in ccRCC." In Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-3362.

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Li, Aihua, Yongfu Gao, Yuekai Zhang, Hongyang Pan, Jackie K. Chan, Ximing J. Yang, and Taiying Chen. "Abstract 3416: IHC assessment of PBRM1 loss in colon and lung carcinomas." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-3416.

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Karki, Menuka, Rahul Jangid, Ramakrishnan Anish, Riyad N. Seervai, Jean-Philippe Bertocchio, Takashi Hotta, Pavlos Msaouel, et al. "Abstract 2042: A cytoskeletal function for PBRM1: reading methylated microtubules to maintain genomic stability." In Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.am2021-2042.

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Jandrig, Burkhard, Odiljon Ikromov, Anica Hoegner, Johann J. Wendler, Martin Schostak, and Hans Krause. "Abstract LB-88: The role of PBRM1 as tumor suppressor gene in renal cell carcinomas." In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-lb-88.

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Schoenfeld, David, William Su, Sakellarios Zairis, Deepti Mathur, Raul Rabadan, and Ramon Parsons. "Abstract A24: PBRM1 alteration in clear cell renal cell carcinoma increases tumorigenicity through ALDH1A1 upregulation." In Abstracts: AACR Special Conference: Chromatin and Epigenetics in Cancer; September 24-27, 2015; Atlanta, GA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.chromepi15-a24.

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Wei, Darmood, Bernard E. Weissman, and Yasumichi Kuwahara. "Abstract 3821: Elucidating the role of PBRM1 in SNF5 regulated gene expression in malignant rhadboid tumors." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-3821.

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Sikder, Rahmat K., Wafik S. El-Deiry, and Philip H. Abbosh. "Abstract 405: PBRM1 re-introduction inPBRM1-mutant kidney cancer cell lines drives an Interferon-γ expression signature." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-405.

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Krause, Hans, Odiljon Ikromov, Eymad All Kamal, Kurt Miller, Martin Schostak, and Burkhard Jandrig. "Abstract 2170: The SWI/SNF nucleosome-remodeling gene PBRM1 - Another tumor suppressor gene in renal cell carcinomas." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-2170.

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Dachuan, Huang, Ong Choon Kiat, Teh Bin Tean, Bernice Wong Huimin, Waraporn Chan-on, Chutima Subimerb, Kyle Furge, and Andrew Futreal. "Abstract 2806: Inactivation of PBRM1, a gene frequently mutated in clear cell renal carcinoma, suppresses tumor growth." In Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-2806.

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