Publications by authors named "Laura Soucek"

50 Publications

Frequent mutations of FBXO11 highlight BCL6 as a therapeutic target in Burkitt lymphoma.

Blood Adv 2021 Oct 8. Epub 2021 Oct 8.

University of Torino, Italy.

The expression of BCL6 in B cell lymphoma can be deregulated by chromosomal translocations, somatic mutations in the promoter regulatory regions or reduced proteasome-mediated degradation. FBXO11 was recently identified as a ubiquitin ligase involved in the degradation of BCL6 and is frequently inactivated in lymphoma or other tumors. Here, we show that FBXO11 mutations are found in 23% of Burkitt lymphoma (BL) patients. FBXO11 mutations impaired BCL6 degradation and the deletion of FBXO11 protein completely stabilized BCL6 levels in human BL cell lines. Conditional deletion of either one or two copies of the FBXO11 gene in mice cooperated with oncogenic MYC and accelerated B cell lymphoma onset, providing experimental evidence that FBXO11 is a haplo-insufficient oncosuppressor in B cell lymphoma. In WT and FBXO11-deficient BL mouse and human cell lines, targeting BCL6 via specific degrader or inhibitors partially impaired lymphoma growth in vitro and in vivo. Inhibition of MYC by the Omomyc mini-protein blocked cell proliferation and increased apoptosis, effects further increased by combined BCL6 targeting. Thus, by validating the functional role of FBXO11 mutations in BL we further highlight the key role of BCL6 in BL biology and provide evidence that innovative therapeutic approaches such as BCL6 degraders and direct MYC inhibition could be exploited as a targeted therapy for BL.
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http://dx.doi.org/10.1182/bloodadvances.2021005682DOI Listing
October 2021

The long journey to bring a Myc inhibitor to the clinic.

J Cell Biol 2021 08 23;220(8). Epub 2021 Jun 23.

Vall d'Hebron Institute of Oncology, Edifici Cellex, Barcelona, Spain.

The oncogene Myc is deregulated in the majority of human tumors and drives numerous hallmarks of cancer. Despite its indisputable role in cancer development and maintenance, Myc is still undrugged. Developing a clinical inhibitor for Myc has been particularly challenging owing to its intrinsically disordered nature and lack of a binding pocket, coupled with concerns regarding potentially deleterious side effects in normal proliferating tissues. However, major breakthroughs in the development of Myc inhibitors have arisen in the last couple of years. Notably, the direct Myc inhibitor that we developed has just entered clinical trials. Celebrating this milestone, with this Perspective, we pay homage to the different strategies developed so far against Myc and all of the researchers focused on developing treatments for a target long deemed undruggable.
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http://dx.doi.org/10.1083/jcb.202103090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240852PMC
August 2021

An "-omycs" Toolbox to Work with MYC.

Methods Mol Biol 2021 ;2318:1-11

Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.

The MYC transcription factor coordinates a wide range of intra- and extracellular processes associated with tissue proliferation and regeneration. While these processes are typically tightly regulated in physiological conditions, they become deregulated in cancer, where MYC is oncogenically activated.The last decade has seen MYC progress from a renowned undruggable target to a hot topic in the cancer therapy field, as proof emerged from mouse models that its inhibition constitutes an effective and broadly applicable approach to fight cancer. However, there are several aspects of MYC biology that still appear to be elusive and maintain the interest in further studying this intriguing protein. Since MYC's discovery, more than four decades ago, multiple strategies have been developed to study it, related to the many and varied facets of its biology. This new version of The Myc gene: Methods and Protocols provides valuable tips from key "inhabitants of the MYC world," which significantly increase the reach of our investigative tools to shed light on the mysteries still surrounding MYC.
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http://dx.doi.org/10.1007/978-1-0716-1476-1_1DOI Listing
August 2021

Integrated requirement of non-specific and sequence-specific DNA binding in Myc-driven transcription.

EMBO J 2021 May 1;40(10):e105464. Epub 2021 Apr 1.

European Institute of Oncology (IEO) - IRCCS, Milan, Italy.

Eukaryotic transcription factors recognize specific DNA sequence motifs, but are also endowed with generic, non-specific DNA-binding activity. How these binding modes are integrated to determine select transcriptional outputs remains unresolved. We addressed this question by site-directed mutagenesis of the Myc transcription factor. Impairment of non-specific DNA backbone contacts caused pervasive loss of genome interactions and gene regulation, associated with increased intra-nuclear mobility of the Myc protein in murine cells. In contrast, a mutant lacking base-specific contacts retained DNA-binding and mobility profiles comparable to those of the wild-type protein, but failed to recognize its consensus binding motif (E-box) and could not activate Myc-target genes. Incidentally, this mutant gained weak affinity for an alternative motif, driving aberrant activation of different genes. Altogether, our data show that non-specific DNA binding is required to engage onto genomic regulatory regions; sequence recognition in turn contributes to transcriptional activation, acting at distinct levels: stabilization and positioning of Myc onto DNA, and-unexpectedly-promotion of its transcriptional activity. Hence, seemingly pervasive genome interaction profiles, as detected by ChIP-seq, actually encompass diverse DNA-binding modalities, driving defined, sequence-dependent transcriptional responses.
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http://dx.doi.org/10.15252/embj.2020105464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126922PMC
May 2021

The Wnt signaling receptor Fzd9 is essential for Myc-driven tumorigenesis in pancreatic islets.

Life Sci Alliance 2021 05 2;4(5). Epub 2021 Mar 2.

Mouse Models of Cancer Therapy Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain

The huge cadre of genes regulated by Myc has obstructed the identification of critical effectors that are essential for Myc-driven tumorigenesis. Here, we describe how only the lack of the receptor Fzd9, previously identified as a Myc transcriptional target, impairs sustained tumor expansion and β-cell dedifferentiation in a mouse model of Myc-driven insulinoma, allows pancreatic islets to maintain their physiological structure and affects Myc-related global gene expression. Importantly, Wnt signaling inhibition in Fzd9-competent mice largely recapitulates the suppression of proliferation caused by Fzd9 deficiency upon Myc activation. Together, our results indicate that the Wnt signaling receptor Fzd9 is essential for Myc-induced tumorigenesis in pancreatic islets.
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http://dx.doi.org/10.26508/lsa.201900490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008953PMC
May 2021

Structural and Biophysical Insights into the Function of the Intrinsically Disordered Myc Oncoprotein.

Cells 2020 04 22;9(4). Epub 2020 Apr 22.

Peptomyc S.L., Edifici Cellex, 08035 Barcelona, Spain.

Myc is a transcription factor driving growth and proliferation of cells and involved in the majority of human tumors. Despite a huge body of literature on this critical oncogene, our understanding of the exact molecular determinants and mechanisms that underlie its function is still surprisingly limited. Indubitably though, its crucial and non-redundant role in cancer biology makes it an attractive target. However, achieving successful clinical Myc inhibition has proven challenging so far, as this nuclear protein is an intrinsically disordered polypeptide devoid of any classical ligand binding pockets. Indeed, Myc only adopts a (partially) folded structure in some contexts and upon interacting with some protein partners, for instance when dimerizing with MAX to bind DNA. Here, we review the cumulative knowledge on Myc structure and biophysics and discuss the implications for its biological function and the development of improved Myc inhibitors. We focus this biophysical walkthrough mainly on the basic region helix-loop-helix leucine zipper motif (bHLHLZ), as it has been the principal target for inhibitory approaches so far.
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http://dx.doi.org/10.3390/cells9041038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226237PMC
April 2020

Blocking Myc to Treat Cancer: Reflecting on Two Decades of Omomyc.

Cells 2020 04 4;9(4). Epub 2020 Apr 4.

Peptomyc S.L., Edifici Cellex, 08035 Barcelona, Spain.

First designed and published in 1998 as a laboratory tool to study Myc perturbation, Omomyc has come a long way in the past 22 years. This dominant negative has contributed to our understanding of Myc biology when expressed, first, in normal and cancer cells, and later in genetically-engineered mice, and has shown remarkable anti-cancer properties in a wide range of tumor types. The recently described therapeutic effect of purified Omomyc mini-protein-following the surprising discovery of its cell-penetrating capacity-constitutes a paradigm shift. Now, much more than a proof of concept, the most characterized Myc inhibitor to date is advancing in its drug development pipeline, pushing Myc inhibition into the clinic.
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http://dx.doi.org/10.3390/cells9040883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226798PMC
April 2020

MYC, MYCL, and MYCN as therapeutic targets in lung cancer.

Expert Opin Ther Targets 2020 02 13;24(2):101-114. Epub 2020 Feb 13.

Peptomyc S.L., Edifici Cellex, Hospital Vall d'Hebron, Barcelona, Spain.

: Lung cancer is the leading cause of cancer-related mortality globally. Despite recent advances with personalized therapies and immunotherapy, the prognosis remains dire and recurrence is frequent. Myc is an oncogene deregulated in human cancers, including lung cancer, where it supports tumorigenic processes and progression. Elevated Myc levels have also been associated with resistance to therapy.: This article summarizes the genomic and transcriptomic studies that compile evidence for (i) MYC, MYCN, and MYCL amplification and overexpression in lung cancer patients, and (ii) their prognostic significance. We collected the most recent literature regarding the development of Myc inhibitors where the emphasis is on those inhibitors tested in lung cancer experimental models and their potential for future clinical application.: The targeting of Myc in lung cancer is potentially an unprecedented opportunity for inhibiting a key player in tumor progression and maintenance and therapeutic resistance. Myc inhibitory strategies are on the path to their clinical application but further work is necessary for the assessment of their use in combination with standard treatment approaches. Given the role of Myc in immune suppression, a significant opportunity may exist in the combination of Myc inhibitors with immunotherapies.
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http://dx.doi.org/10.1080/14728222.2020.1723548DOI Listing
February 2020

MYC Instructs and Maintains Pancreatic Adenocarcinoma Phenotype.

Cancer Discov 2020 04 15;10(4):588-607. Epub 2020 Jan 15.

Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.

The signature features of pancreatic ductal adenocarcinoma (PDAC) are its fibroinflammatory stroma, poor immune activity, and dismal prognosis. We show that acute activation of in indolent pancreatic intraepithelial neoplasm (PanIN) epithelial cells is, alone, sufficient to trigger immediate release of instructive signals that together coordinate changes in multiple stromal and immune-cell types and drive transition to pancreatic adenocarcinomas that share all the characteristic stromal features of their spontaneous human counterpart. We also demonstrate that this -driven PDAC switch is completely and immediately reversible: deactivation/inhibition triggers meticulous disassembly of advanced PDAC tumor and stroma and concomitant death of tumor cells. Hence, both the formation and deconstruction of the complex PDAC phenotype are continuously dependent on a single, reversible switch. SIGNIFICANCE: We show that activation in indolent -induced PanIN epithelium acts as an immediate pleiotropic switch, triggering tissue-specific signals that instruct all the diverse signature stromal features of spontaneous human PDAC. Subsequent deactivation or inhibition immediately triggers a program that coordinately disassembles PDAC back to PanIN..
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http://dx.doi.org/10.1158/2159-8290.CD-19-0435DOI Listing
April 2020

Epigenetic Repression in Tumor-Associated Fibroblasts Impairs Fibrosis and Response to the Antifibrotic Drug Nintedanib in Lung Squamous Cell Carcinoma.

Cancer Res 2020 01 6;80(2):276-290. Epub 2019 Nov 6.

Unit of Biophysics and Bioengineering, Department of Biomedicine, School of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain.

The tumor-promoting fibrotic stroma rich in tumor-associated fibroblasts (TAF) is drawing increased therapeutic attention. Intriguingly, a trial with the antifibrotic drug nintedanib in non-small cell lung cancer reported clinical benefits in adenocarcinoma (ADC) but not squamous cell carcinoma (SCC), even though the stroma is fibrotic in both histotypes. Likewise, we reported that nintedanib inhibited the tumor-promoting fibrotic phenotype of TAFs selectively in ADC. Here we show that tumor fibrosis is actually higher in ADC-TAFs than SCC-TAFs and patient samples. Mechanistically, the reduced fibrosis and nintedanib response of SCC-TAFs was associated with increased promoter methylation of the profibrotic TGFβ transcription factor compared with ADC-TAFs, which elicited a compensatory increase in TGFβ1/SMAD2 activation. Consistently, forcing global DNA demethylation of SCC-TAFs with 5-AZA rescued TGFβ1/SMAD3 activation, whereas genetic downregulation of in ADC-TAFs and control fibroblasts increased TGFβ1/SMAD2 activation, and reduced their fibrotic phenotype and antitumor responses to nintedanib and . Our results also support that smoking and/or the anatomic location of SCC in the proximal airways, which are more exposed to cigarette smoke particles, may prime SCC-TAFs to stronger epigenetic repression, because cigarette smoke condensate selectively increased promoter methylation. Our results unveil that the histotype-specific regulation of tumor fibrosis in lung cancer is mediated through differential promoter methylation in TAFs and provide new mechanistic insights on the selective poor response of SCC-TAFs to nintedanib. Moreover, our findings support that patients with ADC may be more responsive to antifibrotic drugs targeting their stromal TGFβ1/SMAD3 activation. SIGNIFICANCE: This study implicates the selective epigenetic repression of in SCC-TAFs in the clinical failure of nintedanib in SCC and supports that patients with ADC may benefit from antifibrotic drugs targeting stromal TGFβ1/SMAD3.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-0637DOI Listing
January 2020

Targeting Antitumoral Proteins to Breast Cancer by Local Administration of Functional Inclusion Bodies.

Adv Sci (Weinh) 2019 Sep 24;6(18):1900849. Epub 2019 Jul 24.

Institut de Biotecnologia i de Biomedicina Universitat Autònoma de Barcelona Bellaterra 08193 Barcelona Spain.

Two structurally and functionally unrelated proteins, namely Omomyc and p31, are engineered as CD44-targeted inclusion bodies produced in recombinant bacteria. In this unusual particulate form, both types of protein materials selectively penetrate and kill CD44 tumor cells in culture, and upon local administration, promote destruction of tumoral tissue in orthotropic mouse models of human breast cancer. These findings support the concept of bacterial inclusion bodies as versatile protein materials suitable for application in chronic diseases that, like cancer, can benefit from a local slow release of therapeutic proteins.
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http://dx.doi.org/10.1002/advs.201900849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755514PMC
September 2019

Finding MYCure.

Mol Cell Oncol 2019 20;6(5):e1618178. Epub 2019 Jun 20.

Peptomyc S.L., Edifici Cellex, Barcelona, Spain.

Inhibiting the nuclear protein MYC involved in the majority of human cancers has long been considered an impossible mission and several technical challenges have discouraged the development of MYC inhibitory strategies. Nevertheless, in our recent publication in Science Translational Medicine "Intrinsic cell-penetrating activity propels Omomyc from proof of concept to viable anti-MYC therapy", we demonstrate for the first time the feasibility of pharmacological MYC inhibition and using an Omomyc-based mini-protein.
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http://dx.doi.org/10.1080/23723556.2019.1618178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736125PMC
June 2019

Editorial overview: Peptides in cancer.

Curr Opin Pharmacol 2019 08 28;47:iii-v. Epub 2019 Jun 28.

Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Peptomyc S.L., Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.coph.2019.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768800PMC
August 2019

Intrinsic cell-penetrating activity propels Omomyc from proof of concept to viable anti-MYC therapy.

Sci Transl Med 2019 03;11(484)

Peptomyc S.L., Edifici Cellex, Hospital Vall d'Hebron, Barcelona, 08035, Spain.

Inhibiting MYC has long been considered unfeasible, although its key role in human cancers makes it a desirable target for therapeutic intervention. One reason for its perceived undruggability was the fear of catastrophic side effects in normal tissues. However, we previously designed a dominant-negative form of MYC called Omomyc and used its conditional transgenic expression to inhibit MYC function both in vitro and in vivo. MYC inhibition by Omomyc exerted a potent therapeutic impact in various mouse models of cancer, causing only mild, well-tolerated, and reversible side effects. Nevertheless, Omomyc has been so far considered only a proof of principle. In contrast with that preconceived notion, here, we show that the purified Omomyc mini-protein itself spontaneously penetrates into cancer cells and effectively interferes with MYC transcriptional activity therein. Efficacy of the Omomyc mini-protein in various experimental models of non-small cell lung cancer harboring different oncogenic mutation profiles establishes its therapeutic potential after both direct tissue delivery and systemic administration, providing evidence that the Omomyc mini-protein is an effective MYC inhibitor worthy of clinical development.
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http://dx.doi.org/10.1126/scitranslmed.aar5012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522349PMC
March 2019

Inhibition of MYC attenuates tumor cell self-renewal and promotes senescence in SMARCB1-deficient Group 2 atypical teratoid rhabdoid tumors to suppress tumor growth in vivo.

Int J Cancer 2019 04 10;144(8):1983-1995. Epub 2019 Jan 10.

Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.

Loss of SMARCB1 is the hallmark genetic event that characterizes rhabdoid tumors in children. Rhabdoid tumors of the brain (ATRT) occur in young children and are particularly challenging with poor long-term survival. SMARCB1 is a member of the SWI/SNF chromatin remodeling complex that is responsible for determining cellular pluripotency and lineage commitment. The mechanisms by which SMARCB1 deletion results in tumorigenesis remain unclear. Recent studies demonstrate that ATRT consists of 3 genomic subgroups with a subset of poor outcome tumors expressing high BMP and MYC pathway activation. Here we show that MYC occupies distinct promoter loci in ATRT compared to embryonic stem (ES) cells. Furthermore, using human ATRT cell lines, patient-derived cell culture, ex vivo patient-derived tumor, and orthotopic xenograft models, we show that MYC inhibition is a molecular vulnerability in SMARCB1-deleted tumors and that such inhibition effectively suppresses BMP and pluripotency-associated genomic programs, attenuates tumor cell self-renewal, promotes senescence, and inhibits ATRT tumor growth in vivo. Transgenic expression of Omomyc (a bona-fide MYC dominant negative) or chemical inhibition of MYC transcriptomic programs with the BET inhibitor JQ1 phenocopy genetic depletion of MYC, effectively restricting ATRT tumor growth and opening a promising therapeutic avenue for rhabdoid tumors in children.
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http://dx.doi.org/10.1002/ijc.31873DOI Listing
April 2019

BET inhibition is an effective approach against KRAS-driven PDAC and NSCLC.

Oncotarget 2018 Apr 10;9(27):18734-18746. Epub 2018 Apr 10.

Vall d'Hebron Institute of Oncology (VHIO), Edifici Cellex, Hospital Vall d'Hebron, Barcelona, Spain.

Effectively treating KRAS-driven tumors remains an unsolved challenge. The inhibition of downstream signaling effectors is a way of overcoming the issue of direct targeting of mutant KRAS, which has shown limited efficacy so far. Bromodomain and Extra-Terminal (BET) protein inhibition has displayed anti-tumor activity in a wide range of cancers, including KRAS-driven malignancies. Here, we preclinically evaluate the effect of BET inhibition making use of a new BET inhibitor, BAY 1238097, against Pancreatic Ductal Adenocarcinoma (PDAC) and Non-Small Cell Lung Cancer (NSCLC) models harboring RAS mutations both and . Our results demonstrate that BET inhibition displays significant therapeutic impact in genetic mouse models of KRAS-driven PDAC and NSCLC, reducing both tumor area and tumor grade. The same approach also causes a significant reduction in cell number of a panel of RAS-mutated human cancer cell lines (8 PDAC and 6 NSCLC). In this context, we demonstrate that while BET inhibition by BAY 1238097 decreases MYC expression in some cell lines, at least in PDAC cells its anti-tumorigenic effect is independent of MYC regulation. Together, these studies reinforce the use of BET inhibition and prompt the optimization of more efficient and less toxic BET inhibitors for the treatment of KRAS-driven malignancies, which are in urgent therapeutic need.
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http://dx.doi.org/10.18632/oncotarget.24648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922351PMC
April 2018

Myc and Ras, the Bonnie and Clyde of immune evasion.

Transl Cancer Res 2018 Apr;7(Suppl 4):S457-S459

Peptomyc S.L., Centre CELLEX, Barcelona, Spain.

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http://dx.doi.org/10.21037/tcr.2018.03.09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774775PMC
April 2018

Drugging the 'undruggable' cancer targets.

Nat Rev Cancer 2017 08 23;17(8):502-508. Epub 2017 Jun 23.

Vall d'Hebron Institute of Oncology (VHIO), Cellex Centre, Barcelona 08035; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010; and Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.

The term 'undruggable' was coined to describe proteins that could not be targeted pharmacologically. However, progress is being made to 'drug' many of these targets, and therefore more appropriate terms might be 'difficult to drug' or 'yet to be drugged'. Many desirable targets in cancer fall into this category, including the RAS and MYC oncogenes, and pharmacologically targeting these intractable proteins is now a key challenge in cancer research that requires innovation and the development of new technologies. In this Viewpoint article, we asked four scientists working in this field for their opinions on the most crucial advances, as well as the challenges and what the future holds for this important area of research.
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http://dx.doi.org/10.1038/nrc.2017.36DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5945194PMC
August 2017

Biophysical characterization of the b-HLH-LZ of ΔMax, an alternatively spliced isoform of Max found in tumor cells: Towards the validation of a tumor suppressor role for the Max homodimers.

PLoS One 2017 28;12(3):e0174413. Epub 2017 Mar 28.

Département de Biochimie, Faculté de Médecine et des Sciences de la Santé, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada.

It is classically recognized that the physiological and oncogenic functions of Myc proteins depend on specific DNA binding enabled by the dimerization of its C-terminal basic-region-Helix-Loop-Helix-Leucine Zipper (b-HLH-LZ) domain with that of Max. However, a new paradigm is emerging, where the binding of the c-Myc/Max heterodimer to non-specific sequences in enhancers and promoters drives the transcription of genes involved in diverse oncogenic programs. Importantly, Max can form a stable homodimer even in the presence of c-Myc and bind DNA (specific and non-specific) with comparable affinity to the c-Myc/Max heterodimer. Intriguingly, alterations in the Max gene by germline and somatic mutations or changes in the gene product by alternative splicing (e.g. ΔMax) were recently associated with pheochromocytoma and glioblastoma, respectively. This has led to the proposition that Max is, by itself, a tumor suppressor. However, the actual mechanism through which it exerts such an activity remains to be elucidated. Here, we show that contrary to the WT motif, the b-HLH-LZ of ΔMax does not homodimerize in the absence of DNA. In addition, although ΔMax can still bind the E-box sequence as a homodimer, it cannot bind non-specific DNA in that form, while it can heterodimerize with c-Myc and bind E-box and non-specific DNA as a heterodimer with high affinity. Taken together, our results suggest that the WT Max homodimer is important for attenuating the binding of c-Myc to specific and non-specific DNA, whereas ΔMax is unable to do so. Conversely, the splicing of Max into ΔMax could provoke an increase in overall chromatin bound c-Myc. According to the new emerging paradigm, the splicing event and the stark reduction in homodimer stability and DNA binding should promote tumorigenesis impairing the tumor suppressor activity of the WT homodimer of Max.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0174413PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5370111PMC
September 2017

Strategies to Inhibit Myc and Their Clinical Applicability.

Front Cell Dev Biol 2017 23;5:10. Epub 2017 Feb 23.

Vall d'Hebron Institute of Oncology, Edifici Cellex, Hospital Vall d'HebronBarcelona, Spain; Peptomyc, Edifici Cellex, Hospital Vall d'HebronBarcelona, Spain; Institució Catalana de Recerca i Estudis AvançatsBarcelona, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de BarcelonaBellaterra, Spain.

Myc is an oncogene deregulated in most-perhaps all-human cancers. Each Myc family member, c-, L-, and N-Myc, has been connected to tumor progression and maintenance. Myc is recognized as a "most wanted" target for cancer therapy, but has for many years been considered undruggable, mainly due to its nuclear localization, lack of a defined ligand binding site, and physiological function essential to the maintenance of normal tissues. The challenge of identifying a pharmacophore capable of overcoming these hurdles is reflected in the current absence of a clinically-viable Myc inhibitor. The first attempts to inhibit Myc used antisense technology some three decades ago, followed by small molecule inhibitors discovered through "classical" compound library screens. Notable breakthroughs proving the feasibility of systemic Myc inhibition were made with the Myc dominant negative mutant Omomyc, showing both the great promise in targeting this infamous oncogene for cancer treatment as well as allaying fears about the deleterious side effects that Myc inhibition might have on normal proliferating tissues. During this time many other strategies have appeared in an attempt to drug the undruggable, including direct and indirect targeting, knockdown, protein/protein and DNA interaction inhibitors, and translation and expression regulation. The inhibitors range from traditional small molecules to natural chemicals, to RNA and antisense, to peptides and miniproteins. Here, we briefly describe the many approaches taken so far, with a particular focus on their potential clinical applicability.
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http://dx.doi.org/10.3389/fcell.2017.00010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5322154PMC
February 2017

Interrogating open issues in cancer precision medicine with patient-derived xenografts.

Nat Rev Cancer 2017 04 20;17(4):254-268. Epub 2017 Jan 20.

EurOPDX Consortium and are at The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.

Patient-derived xenografts (PDXs) have emerged as an important platform to elucidate new treatments and biomarkers in oncology. PDX models are used to address clinically relevant questions, including the contribution of tumour heterogeneity to therapeutic responsiveness, the patterns of cancer evolutionary dynamics during tumour progression and under drug pressure, and the mechanisms of resistance to treatment. The ability of PDX models to predict clinical outcomes is being improved through mouse humanization strategies and the implementation of co-clinical trials, within which patients and PDXs reciprocally inform therapeutic decisions. This Opinion article discusses aspects of PDX modelling that are relevant to these questions and highlights the merits of shared PDX resources to advance cancer medicine from the perspective of EurOPDX, an international initiative devoted to PDX-based research.
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http://dx.doi.org/10.1038/nrc.2016.140DOI Listing
April 2017

Ibrutinib repurposing: from B-cell malignancies to solid tumors.

Oncoscience 2016 10;3(5-6):147-8. Epub 2016 Jun 10.

Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain.

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http://dx.doi.org/10.18632/oncoscience.310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4965256PMC
August 2016

Growth suppression by MYC inhibition in small cell lung cancer cells with TP53 and RB1 inactivation.

Oncotarget 2016 May;7(21):31014-28

Genomics and Epigenomics of Cancer Prediction Program, Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Campus Can Ruti, Barcelona, Spain.

Small cell lung cancer (SCLC) is the most aggressive type of lung cancer with high mortality. One of the MYC family genes, MYC, MYCL or MYCN, is amplified in ~20% of the SCLCs; therefore, MYC proteins are potential therapeutic targets in SCLC patients. We investigated the therapeutic impact of Omomyc, a MYC dominant negative, in a panel of SCLC cell lines. Strikingly, Omomyc suppressed the growth of all tested cell lines by inducing cell cycle arrest and/or apoptosis. Induction of G1 arrest by Omomyc was found to be dependent on the activation of CDKN1A, in part, through the TP73 pathway. Our results strongly indicate that SCLC cells carrying amplification of MYC, MYCL or MYCN are addicted to MYC function, suggesting that MYC targeting would be an efficient therapeutic option for SCLC patients.
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http://dx.doi.org/10.18632/oncotarget.8826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5058735PMC
May 2016

Live or Die: Choice Mechanisms in Stressed Cells.

Mediators Inflamm 2015 8;2015:454863. Epub 2015 Oct 8.

Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Section of Histology and Medical Embryology, Sapienza University of Rome, 00161 Rome, Italy.

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http://dx.doi.org/10.1155/2015/454863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4609861PMC
August 2016

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Carcinogenesis 2015 Jun;36 Suppl 1:S254-96

Superfund Research Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27560, USA.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.
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http://dx.doi.org/10.1093/carcin/bgv039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480130PMC
June 2015

The effect of environmental chemicals on the tumor microenvironment.

Carcinogenesis 2015 Jun;36 Suppl 1:S160-83

Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.

Potentially carcinogenic compounds may cause cancer through direct DNA damage or through indirect cellular or physiological effects. To study possible carcinogens, the fields of endocrinology, genetics, epigenetics, medicine, environmental health, toxicology, pharmacology and oncology must be considered. Disruptive chemicals may also contribute to multiple stages of tumor development through effects on the tumor microenvironment. In turn, the tumor microenvironment consists of a complex interaction among blood vessels that feed the tumor, the extracellular matrix that provides structural and biochemical support, signaling molecules that send messages and soluble factors such as cytokines. The tumor microenvironment also consists of many host cellular effectors including multipotent stromal cells/mesenchymal stem cells, fibroblasts, endothelial cell precursors, antigen-presenting cells, lymphocytes and innate immune cells. Carcinogens can influence the tumor microenvironment through effects on epithelial cells, the most common origin of cancer, as well as on stromal cells, extracellular matrix components and immune cells. Here, we review how environmental exposures can perturb the tumor microenvironment. We suggest a role for disrupting chemicals such as nickel chloride, Bisphenol A, butyltins, methylmercury and paraquat as well as more traditional carcinogens, such as radiation, and pharmaceuticals, such as diabetes medications, in the disruption of the tumor microenvironment. Further studies interrogating the role of chemicals and their mixtures in dose-dependent effects on the tumor microenvironment could have important general mechanistic implications for the etiology and prevention of tumorigenesis.
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http://dx.doi.org/10.1093/carcin/bgv035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4565612PMC
June 2015

Ibrutinib exerts potent antifibrotic and antitumor activities in mouse models of pancreatic adenocarcinoma.

Cancer Res 2015 Apr;75(8):1675-81

Vall d'Hebron Institute of Oncology (VHIO), Edifici Mediterrània, Hospital Vall d'Hebron, Barcelona, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense stromal fibroinflammatory reaction that is a major obstacle to effective therapy. The desmoplastic stroma comprises many inflammatory cells, in particular mast cells as key components of the PDAC microenvironment, and such infiltration correlates with poor patient outcome. Indeed, it has been hypothesized that stromal ablation is critical to improve clinical response in patients with PDAC. Ibrutinib is a clinically approved Bruton's tyrosine kinase inhibitor that inhibits mast cells and tumor progression in a mouse model of β-cell tumorigenesis. Here, we show that ibrutinib is highly effective at limiting the growth of PDAC in both transgenic mouse and patient-derived xenograft models of the disease. In these various experimental settings, ibrutinib effectively diminished fibrosis, extended survival, and improved the response to clinical standard-of-care therapy. Our results offer a preclinical rationale to immediately evaluate the clinical efficacy of ibrutinib in patients with PDAC.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-2852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773609PMC
April 2015

The estrogen receptor fusion system in mouse models: a reversible switch.

Cold Spring Harb Protoc 2015 Mar 2;2015(3):227-34. Epub 2015 Mar 2.

Vall d'Hebron Institute of Oncology (VHIO), Barcelona 08035, Spain; Universitat Autònoma de Barcelona, 08193 Bellaterra (Cerdanyola del Vallès), Spain;

Reversible regulatory mouse models have significantly contributed to our understanding of normal tissue and cancer biology, providing the opportunity to temporally control initiation, progression, and evolution of physiological and pathological events. The tamoxifen inducible system, one of the best-characterized "reversible switch" models, has a number of beneficial features. In this system, the hormone-binding domain of the mammalian estrogen receptor is used as a heterologous regulatory domain. Upon ligand binding, the receptor is released from its inhibitory complex and the fusion protein becomes functional. We summarize the advantages and drawbacks of the system, describe several mouse models that rely on it, and discuss potential improvements that could render it even more useful and versatile.
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http://dx.doi.org/10.1101/pdb.top069815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768801PMC
March 2015

Tamoxifen administration to mice.

Cold Spring Harb Protoc 2015 Mar 2;2015(3):269-71. Epub 2015 Mar 2.

Vall d'Hebron Institute of Oncology (VHIO), Barcelona 08035, Spain; Universitat Autònoma de Barcelona, 08193 Bellaterra (Cerdanyola del Vallès), Spain;

The strategy of fusing a protein of interest to a hormone-binding domain (HBD) of a steroid hormone receptor allows fine control of the activity of the fused protein. Such fusion proteins are inactive in the absence of ligand, because they are complexed with a variety of intracellular polypeptides. Upon ligand binding, the receptor is released from its inhibitory complex and the fusion protein becomes functional. In the murine estrogen receptor (ER) fusion system, proteins are fused to the HBD of the ER. The system relies on the use of a mutant ER known as ER(TAM). Compared to the wild-type HBD, ER(TAM) has 1000-fold lower affinity for estrogen, yet remains responsive to activation by the synthetic steroid 4-hydroxytamoxifen (4-OHT). Because 4-OHT is expensive, animals can be treated with the cheaper precursor tamoxifen, which is converted into 4-OHT by a liver enzyme. Here we present an overview of the methods used to deliver tamoxifen to mice. The most used method is intraperitoneal injection, because the amount of administered compound can be better controlled, but delivery by oral gavage is also possible. For short-term and immediate-effect studies or when conversion of tamoxifen by the liver is to be avoided, 4-OHT can be used directly.
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http://dx.doi.org/10.1101/pdb.prot077966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773604PMC
March 2015
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