subject:(PBRM1)

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1. Morel, Daphné. Identifying Synthetic Lethal and Selective Approaches to Target PBRM1-Deficiency in Clear Cell Renal Cell Carcinoma : Exploration de stratégies thérapeutiques ciblant la déficience en PBRM1 dans les carcinomes rénaux à cellules claires.

Degree: Docteur es, Aspects moléculaires et cellulaires de la biologie, 2020, université Paris-Saclay

URL: http://www.theses.fr/2020UPASL017

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.

Advisors/Committee Members: Postel-Vinay, Sophie (thesis director), Deutsch, Eric (thesis director).

Subjects/Keywords: Pbrm1; Létalité synthétique; Inhibiteurs de PARP; Cancer du rein; Kidney cancer; Synthetic lethality; PARP inhibitors; Pbrm1

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Morel, D. (2020). Identifying Synthetic Lethal and Selective Approaches to Target PBRM1-Deficiency in Clear Cell Renal Cell Carcinoma : Exploration de stratégies thérapeutiques ciblant la déficience en PBRM1 dans les carcinomes rénaux à cellules claires. (Doctoral Dissertation). université Paris-Saclay. Retrieved from http://www.theses.fr/2020UPASL017

Chicago Manual of Style (16^th Edition):

Morel, Daphné. “Identifying Synthetic Lethal and Selective Approaches to Target PBRM1-Deficiency in Clear Cell Renal Cell Carcinoma : Exploration de stratégies thérapeutiques ciblant la déficience en PBRM1 dans les carcinomes rénaux à cellules claires.” 2020. Doctoral Dissertation, université Paris-Saclay. Accessed February 28, 2021. http://www.theses.fr/2020UPASL017.

MLA Handbook (7^th Edition):

Vancouver:

Morel D. Identifying Synthetic Lethal and Selective Approaches to Target PBRM1-Deficiency in Clear Cell Renal Cell Carcinoma : Exploration de stratégies thérapeutiques ciblant la déficience en PBRM1 dans les carcinomes rénaux à cellules claires. [Internet] [Doctoral dissertation]. université Paris-Saclay; 2020. [cited 2021 Feb 28]. Available from: http://www.theses.fr/2020UPASL017.

Council of Science Editors:

Morel D. Identifying Synthetic Lethal and Selective Approaches to Target PBRM1-Deficiency in Clear Cell Renal Cell Carcinoma : Exploration de stratégies thérapeutiques ciblant la déficience en PBRM1 dans les carcinomes rénaux à cellules claires. [Doctoral Dissertation]. université Paris-Saclay; 2020. Available from: http://www.theses.fr/2020UPASL017

Michigan Technological University

2. Hopson, Sarah. Heterologous Expression and Purification of Full-Length Human Polybromo-1 Protein.

Degree: PhD, Department of Chemistry, 2017, Michigan Technological University

URL: https://digitalcommons.mtu.edu/etdr/436

Over the past decade, it has become apparent that the human polybromo-1 protein (BAF180) has a critical role in cancer. BAF180 is known to be a driver mutation in clear cell renal cell carcinoma, where it has been found to be mutated in approximately 40% of cases. Mutations have also been found in several other cancers, including intrahepatic cholangiocarcinomas and epithelioid sarcomas. BAF180 is the chromatin targeting subunit of the PBAF (Polybromo-associated BRG1-associated factor) chromatin remodeling complex, a role facilitated by its nine domains: six bromodomains, which recognize and bind to acetylated lysines on histones; two BAH (bromo-adjacent homology) domains, found to be critical for PCNA ubiquitination following DNA damage; and one HMG (high mobility group) box, the DNA binding component. Furthermore, proper expression of BAF180 has also been linked to cardiac development and cell cycle regulation. Despite these associations, the molecular level interactions of full-length BAF180 have yet to be studied; only the phenomenological effects of BAF180 deficiency/mutation have been studied. It is crucial that we understand the binding dynamics and specificities of wild type and mutated BAF180, since it is the recognition component of PBAF. Expression of the recombinant full-length BAF180 protein has been difficult because of the complex nature of this protein, its unusual codon usage, and size. After E. coli expression failed, other expression systems were investigated and the yeast Pichia pastoris was chosen. Pichia was chosen for several reasons: its codon usage is similar to that of BAF180 and it is a eukaryotic system possessing eukaryotic protein folding machinery and capable of performing post-translational modifications. Under control of the GAP promoter, full-length BAF180 has been successfully expressed in Pichia pastoris. This is the first time that full-length BAF180 has been cloned and expressed in a heterologous host. It was purified using anion exchange chromatography. The ability to express and purify full-length BAF180 is a huge first step towards increasing the understanding of the molecular mechanisms of this protein and its association with cancer development. Advisors/Committee Members: Martin Thompson.

Subjects/Keywords: recombinant protein expression and purification; human polybromo-1; BAF180; PBRM1; hPB1; Pichia pastoris; Biochemistry; Molecular Biology

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Hopson, S. (2017). Heterologous Expression and Purification of Full-Length Human Polybromo-1 Protein. (Doctoral Dissertation). Michigan Technological University. Retrieved from https://digitalcommons.mtu.edu/etdr/436

Chicago Manual of Style (16^th Edition):

Hopson, Sarah. “Heterologous Expression and Purification of Full-Length Human Polybromo-1 Protein.” 2017. Doctoral Dissertation, Michigan Technological University. Accessed February 28, 2021. https://digitalcommons.mtu.edu/etdr/436.

MLA Handbook (7^th Edition):

Hopson, Sarah. “Heterologous Expression and Purification of Full-Length Human Polybromo-1 Protein.” 2017. Web. 28 Feb 2021.

Vancouver:

Hopson S. Heterologous Expression and Purification of Full-Length Human Polybromo-1 Protein. [Internet] [Doctoral dissertation]. Michigan Technological University; 2017. [cited 2021 Feb 28]. Available from: https://digitalcommons.mtu.edu/etdr/436.

Council of Science Editors:

Hopson S. Heterologous Expression and Purification of Full-Length Human Polybromo-1 Protein. [Doctoral Dissertation]. Michigan Technological University; 2017. Available from: https://digitalcommons.mtu.edu/etdr/436

3. Högner, Anica. Role of the tumor suppressor genes PBRM1 and VHL in clear cell renal cell carcinogenesis.

Degree: 2018, Freie Universität Berlin

URL: http://dx.doi.org/10.17169/refubium-1401

Background In clear cell renal cell carcinoma (ccRCC), PBRM1 (Polybromo-1 gene) harbors about 40% truncating somatic mutations and was identified as the second most frequently mutated two-hit tumor suppressor gene, next to VHL (von Hippel-Lindau gene). Although sporadic inactivation of VHL is predominant in ccRCC (~ 90%), PBRM1 may have a putative gatekeeper function in cases where VHL loss alone is insufficient for ccRCC tumorigenesis. The aim of this study was to identify the impact of PBRM1 and VHL expression at mRNA and protein levels on clinicopathological features and patient outcome in ccRCC. Methods In fresh frozen tumor and adjacent normal tissue from 70 patients who underwent radical nephrectomy, immunohistochemical stainings, Western blotting and qPCR analysis of PBRM1 and VHL were performed. In addition, a tissue micro array (TMA) consisting of 326 ccRCC patient samples was used to identify the effect of loss of PBRM1 and VHL immunohistological expression on clinicopathological factors and patient overall survival. Results In both groups of fresh frozen ccRCC and TMA samples, men were more affected by ccRCC compared to women (68.1% / 64.4%). Large tumors of pT3/4 stage prevailed in fresh frozen samples (pT3/4, n = 38/70), whereas small tumors predominated in TMA samples (pT1/2, n = 212/326). In the majority of ccRCC fresh frozen tumor samples, both PBRM1 and VHL mRNA were significantly down-regulated (77.6% / 80.6%). In this group, 21.4% of frozen tumors showed simultaneous weak PBRM1 and VHL protein expression in immunohistochemistry. However, 60.4% of the TMA samples showed weak PBRM1 and VHL immunohistochemical expression which was correlated significantly (P < 0.001). In view of the impact of PBRM1 and VHL expression in immunohistochemistry on clinicopathological features, weak PBRM1 and VHL expression was associated with higher Fuhrman grade, significantly (P = 0.012 and 0.024, respectively). Interestingly, only weak VHL expression was associated with larger tumors (pT 3/4, P = 0.023). Accordingly, there was an association of weak VHL immunohistological expression with decreased patient overall survival (P = 0.013), while PBRM1 expression did not affect the patient’s overall survival. Conclusions Our results indicate a correlation of reduced expression of PBRM1 and VHL with an increased tumor aggressiveness. We identified low VHL expression as an independent risk factor for worse patient outcome. Advisors/Committee Members: female (gender), N.N. (firstReferee), N.N. (furtherReferee).

Subjects/Keywords: PBRM1; VHL; Immunohistochemistry; Tissue microarray; Clear cell renal cell carcinoma; 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit

…Andreas Erbersdobler, Andreas Patzak, Ergin Kilic „PBRM1 and VHL expression correlate in human… …Einzelnen: Die gemeinsame Projekt-Idee für die Untersuchung des Tumorsuppressorgens PBRM1 im… …PBRM1 zu entwickeln, welches zunächst die histologische Expression von PBRM1 und VHL auf… …etablierte das PBRM1- und VHL -Färbeprotokoll im Institut für Vegetative Physiologie der Charité… …Expressionsstärke von PBRM1 und VHL. Über das Institut für Pathologie bekam ich die Möglichkeit, 14 Tissue…

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Högner, A. (2018). Role of the tumor suppressor genes PBRM1 and VHL in clear cell renal cell carcinogenesis. (Thesis). Freie Universität Berlin. Retrieved from http://dx.doi.org/10.17169/refubium-1401

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Högner, Anica. “Role of the tumor suppressor genes PBRM1 and VHL in clear cell renal cell carcinogenesis.” 2018. Thesis, Freie Universität Berlin. Accessed February 28, 2021. http://dx.doi.org/10.17169/refubium-1401.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Högner, Anica. “Role of the tumor suppressor genes PBRM1 and VHL in clear cell renal cell carcinogenesis.” 2018. Web. 28 Feb 2021.

Vancouver:

Högner A. Role of the tumor suppressor genes PBRM1 and VHL in clear cell renal cell carcinogenesis. [Internet] [Thesis]. Freie Universität Berlin; 2018. [cited 2021 Feb 28]. Available from: http://dx.doi.org/10.17169/refubium-1401.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Högner A. Role of the tumor suppressor genes PBRM1 and VHL in clear cell renal cell carcinogenesis. [Thesis]. Freie Universität Berlin; 2018. Available from: http://dx.doi.org/10.17169/refubium-1401

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

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