Research publications

Found 5 publicacions matching the indicated search criteria.
Montagut AM, Armengol M, de Pablo GG, Estrada-Tejedor R, Borrell JI, Roué G

Recent advances in the pharmacological targeting of ubiquitin-regulating enzymes in cancer.

Semin Cell Dev Biol 17 Feb 2022, . Epub 17 Feb 2022
As a post-translational modification that has pivotal roles in protein degradation, ubiquitination ensures that intracellular proteins act in a precise spatial and temporal manner to regulate diversified cellular processes. Perturbation of the ubiquitin system contributes directly to the onset and progression of a wide variety of diseases, including various subtypes of cancer. This highly regulated system has been for years an active research area for drug discovery that is exemplified by several approved drugs. In this review, we will provide an update of the main breakthrough scientific discoveries that have been leading the clinical development of ubiquitin-targeting therapies in the last decade, with a special focus on E1 and E3 modulators. We will further discuss the unique challenges of identifying new potential therapeutic targets within this ubiquitous and highly complex machinery, based on available crystallographic structures, and explore chemical approaches by which these challenges might be met.
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Ribeiro ML, Reyes-Garau D, Vinyoles M, Profitos-Peleja N, Santos JC, Armengol M, Fernández-Serrano M, Sedo Mor A, Bech-Serra JJ, Blecua P, Musulen E, De La Torre C, Miskin HP, Esteller M, Bosch F, Menéndez P, Normant E, Roué G

Antitumor activity of the novel BTK inhibitor TG-1701 is associated with disruption of Ikaros signaling in patients with B-cell non-Hodgkin lymphoma.

Clin Cancer Res 2 Dec 2021, . Epub 22 Sep 2021
Purpose: Despite the remarkable activity of BTK inhibitors (BTKi) in relapsed B-cell non-Hodgkin lymphoma (B-NHL), no clinically-relevant biomarker has been associated to these agents so far. The relevance of phosphoproteomic profiling for the early identification of BTKi responders remains underexplored. Experimental design: A set of six clinical samples from an ongoing phase 1 trial dosing chronic lymphocytic leukemia (CLL) patients with TG-1701, a novel irreversible and highly specific BTKi, were characterized by phosphoproteomic and RNA-seq analysis. The activity of TG-1701 was evaluated in a panel of eleven B-NHL cell lines and mouse xenografts, including two NFκB- and BTKC481S-driven BTKi resistant models. Biomarker validation and signal transduction analysis were conducted through real-time PCR, western blot, immunostaining and gene knock-out (KO) experiments. Results: A non-supervised, phosphoproteomic-based clustering did match the early clinical outcomes of CLL patients and separated a group of "early-responders" from a group of "late-responders". This clustering was based on a selected list of 96 phosphosites with Ikaros-pSer442/445 as a potential biomarker for TG-1701 efficacy. TG-1701 treatment was further shown to blunt Ikaros gene signature, including YES1 and MYC, in early-responder patients as well as in BTKi-sensitive B-NHL cell lines and xenografts. In contrast, Ikaros nuclear activity and signaling remained unaffected by the drug in vitro and in vivo, in late-responder patients and in BTKC481S, BTKKO and non-canonical NFκB models. Conclusions: These data validate phosphoproteomic as a valuable tool for the early detection of response to BTK inhibition in the clinic, and for the determination of drug mechanism of action.
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Dlouhy I, Armengol M, Recasens-Zorzo C, Ribeiro ML, Pérez-Galán P, Bosch F, López-Guillermo A, Roué G

Interleukin-1 receptor associated kinase 1/4 and bromodomain and extraterminal inhibitions converge on NF-κB blockade and display synergistic antitumoral activity in activated B-cell subset of diffuse large B-cell lymphoma with

Haematologica 13 May 2021, . Epub 13 May 2021
Abstract not available.
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Marc Armengol, Juliana Carvalho Santos, Miranda Fernández-Serrano, Núria Profitós-Pelejà, Marcelo Lima Ribeiro, Gaël Roué

Immune-Checkpoint Inhibitors in B-Cell Lymphoma

Cancers 2021, 13(2), 214 8 Jan 2021, .
For years, immunotherapy has been considered a viable and attractive treatment option for patients with cancer. Among the immunotherapy arsenal, the targeting of intratumoral immune cells by immune-checkpoint inhibitory agents has recently revolutionised the treatment of several subtypes of tumours. These approaches, aimed at restoring an effective antitumour immunity, rapidly reached the market thanks to the simultaneous identification of inhibitory signals that dampen an effective antitumor response in a large variety of neoplastic cells and the clinical development of monoclonal antibodies targeting checkpoint receptors. Leading therapies in solid tumours are mainly focused on the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) pathways. These approaches have found a promising testing ground in both Hodgkin lymphoma and non-Hodgkin lymphoma, mainly because, in these diseases, the malignant cells interact with the immune system and commonly provide signals that regulate immune function. Although several trials have already demonstrated evidence of therapeutic activity with some checkpoint inhibitors in lymphoma, many of the immunologic lessons learned from solid tumours may not directly translate to lymphoid malignancies. In this sense, the mechanisms of effective antitumor responses are different between the different lymphoma subtypes, while the reasons for this substantial difference remain partially unknown. This review will discuss the current advances of immune-checkpoint blockade therapies in B-cell lymphoma and build a projection of how the field may evolve in the near future. In particular, we will analyse the current strategies being evaluated both preclinically and clinically, with the aim of fostering the use of immune-checkpoint inhibitors in lymphoma, including combination approaches with chemotherapeutics, biological agents and/or different immunologic therapies.
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Ribeiro ML, Reyes-Garau D, Armengol M, Fernández-Serrano M, Roué G

Recent Advances in the Targeting of Epigenetic Regulators in B-Cell Non-Hodgkin Lymphoma.

Front Genet 2019, 10 986. Epub 16 Oct 2019
In the last 10 years, major advances have been made in the diagnosis and development of selective therapies for several blood cancers, including B-cell non-Hodgkin lymphoma (B-NHL), a heterogeneous group of malignancies arising from the mature B lymphocyte compartment. However, most of these entities remain incurable and current treatments are associated with variable efficacy, several adverse events, and frequent relapses. Thus, new diagnostic paradigms and novel therapeutic options are required to improve the prognosis of patients with B-NHL. With the recent deciphering of the mutational landscapes of B-cell disorders by high-throughput sequencing, it came out that different epigenetic deregulations might drive and/or promote B lymphomagenesis. Consistently, over the last decade, numerous epigenetic drugs (or epidrugs) have emerged in the clinical management of B-NHL patients. In this review, we will present an overview of the most relevant epidrugs tested and/or used so far for the treatment of different subtypes of B-NHL, from first-generation epigenetic therapies like histone acetyl transferases (HDACs) or DNA-methyl transferases (DNMTs) inhibitors to new agents showing selectivity for proteins that are mutated, translocated, and/or overexpressed in these diseases, including EZH2, BET, and PRMT. We will dissect the mechanisms of action of these epigenetic inhibitors, as well as the molecular processes underlying their lack of efficacy in refractory patients. This review will also provide a summary of the latest strategies being employed in preclinical and clinical settings, and will point out the most promising lines of investigation in the field.
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