Erika Serrano

Inhibition of Myc family proteins eradicates KRas-driven lung cancer in mice.

The principal reason for failure of targeted cancer therapies is the emergence of resistant clones that regenerate the tumor. Therapeutic efficacy therefore depends on not only how effectively a drug inhibits its target, but also the innate or adaptive functional redundancy of that target and its attendant pathway. In this regard, the Myc transcription factors are intriguing therapeutic targets because they serve the unique and irreplaceable role of coordinating expression of the many diverse genes that, together, are required for somatic cell proliferation. Furthermore, Myc expression is deregulated in most-perhaps all-cancers, underscoring its irreplaceable role in proliferation. We previously showed in a preclinical mouse model of non-small-cell lung cancer that systemic Myc inhibition using the dominant-negative Myc mutant Omomyc exerts a dramatic therapeutic impact, triggering rapid regression of tumors with only mild and fully reversible side effects. Using protracted episodic expression of Omomyc, we now demonstrate that metronomic Myc inhibition not only contains Ras-driven lung tumors indefinitely, but also leads to their progressive eradication. Hence, Myc does indeed serve a unique and nondegenerate role in lung tumor maintenance that cannot be complemented by any adaptive mechanism, even in the most aggressive p53-deficient tumors. These data endorse Myc as a compelling cancer drug target.

Myc inhibition is effective against glioma and reveals a role for Myc in proficient mitosis

Gliomas are the most common primary tumours affecting the adult central nervous system and respond poorly to standard therapy. Myc is causally implicated in most human tumours and the majority of glioblastomas have elevated Myc levels. Using the Myc dominant negative Omomyc, we previously showed that Myc inhibition is a promising strategy for cancer therapy. Here, we preclinically validate Myc inhibition as a therapeutic strategy in mouse and human glioma, using a mouse model of spontaneous multifocal invasive astrocytoma and its derived neuroprogenitors, human glioblastoma cell lines, and patient-derived tumours both in vitro and in orthotopic xenografts. Across all these experimental models we find that Myc inhibition reduces proliferation, increases apoptosis and remarkably, elicits the formation of multinucleated cells that then arrest or die by mitotic catastrophe, revealing a new role for Myc in the proficient division of glioma cells.

Ibrutinib Exerts Potent Antifibrotic and Antitumor Activities in Mouse Models of Pancreatic Adenocarcinoma

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 Brutons 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.

Influenza A virus subtypes in wild birds in North-Eastern Spain (Catalonia).

Since the spread of H5N1 highly pathogenic avian influenza virus in 2005, many surveillance programmes have been initiated in poultry and wild birds worldwide. This study describes for the first time the detection of different subtypes of avian influenza viruses (AIV) in wild birds in the West Mediterranean area (Catalonia, North-Eastern Spain). During a 3-year period (from mid-2006 to mid-2009), 1374 birds from 16 different families were examined, and a total of 62 AIV were detected by means of a real-time reverse transcriptase PCR assay. AIV were more frequently detected in Anatidae, Phoenicopteridae, Rallidae and Laridae families. Of the 62 positive samples, 28 AIV could be isolated in embryonated eggs. All isolates were subtyped by haemagglutinin and neuraminidase inhibition techniques and 10 different haemagglutinins (HA) and 7 neuraminidases (NA) were found in 13 different subtype combinations. The most common combinations were H4N6 (22.2%) and H1N1 (18.5%). The HA and NA gene sequences of different AIV subtypes were compared and aligned with those available AIV strains from genome databases. Our studies on AIV phylogenetic analysis revealed that all AIV genes sequenced from wild birds in North-Eastern Spain clustered within Eurasian avian clades, including the sequences of H8, N4 and N5 genes analyzed for the first time in Europe. The results contribute to the understanding of AIV in the Mediterranean area and in Europe.

Abstract PR10: Preclinical validation of Myc inhibition by a new generation of Omomyc-based cell penetrating peptides

Deregulated Myc is associated with most human cancers suggesting that its inhibition would be a useful therapeutic strategy. Indeed, we have shown that Myc inhibition displays extraordinary therapeutic benefit in various transgenic mouse models of cancer (i.e skin, lung, pancreatic cancer and glioma) and causes only mild, well-tolerated and reversible side effects in normal tissues. For these studies we employed a dominant negative inhibitor of Myc, called Omomyc, which proved to be the most effective inhibitor of Myc transactivation function both in vitro and in vivo. Omomyc has so far been utilized exclusively as a transgene and served as a proof of principle. Here we report the exciting finding that Omomyc-based Cell Penetrating Peptides (CPPs) are a novel, state-of-the-art method for directly utilizing Omomyc itself (and similar peptides) to treat tumors in the lung and brain, where the peptides biodistribute after intranasal administration. We provide a comprehensive preclinical validation of this innovative therapeutic approach for pharmacological inhibition of Myc in cancer cell lines of different origin and genetic make-up, as well as in a mouse model of Non-Small-Cell Lung Cancer (NSCLC), where the Omomyc-CPPs, like their transgenic counterpart before, display a dramatic therapeutic impact. Citation Format: Marie-eve Beaulieu, Jonathan Whitfield, Daniel Masso-Valles, Toni Jauset, Erika Serrano, Martin Montagne, Loika Maltais, Cynthia Tremblay, Pierre Lavigne, Laura Soucek. Preclinical validation of Myc inhibition by a new generation of Omomyc-based cell penetrating peptides. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr PR10.

Abstract 2645: Preclinical validation of Myc inhibition by a new generation of Omomyc-based inhibitors

Deregulated Myc is associated with most human cancers suggesting that its inhibition would be a useful therapeutic strategy. Indeed, we have shown that Myc inhibition displays extraordinary therapeutic benefit in various transgenic mouse models of cancer (i.e. skin, lung, pancreatic cancer and glioma) and causes only mild, well-tolerated and reversible side effects in normal tissues. Furthermore, we demonstrated that Myc has a non-degenerate function in cancer that cannot be replaced by other pathways, even in the most aggressive p53-null tumors. Therefore, Myc could be targeted safely and successfully without eliciting resistance to therapy. For these studies we employed a dominant negative inhibitor of Myc, called Omomyc, which is an effective inhibitor of Myc transactivation function both in vitro and in vivo. Omomyc has so far been utilized exclusively as a transgene and served as a successful proof of principle. Here we discuss our current research with Omomyc and our efforts to develop a clinically viable approach to Myc inhibition. One is based on the direct use of Omomyc itself as a peptide since we have discovered that it natively possesses cell-penetrating activity and it rapidly biodistributes to the lung and brain after intranasal administration. We are finding that the Omomyc peptide - like its transgenic counterpart before - has a therapeutic impact and we are continuing with the preclinical validation of this innovative therapeutic approach to pharmacological Myc inhibition. The second approach takes advantage of state-of-the-art nanocarrier technology to deliver Omomyc systemically, that can be combined with tumour-targeting ligands. These two novel Myc inhibition strategies have the potential to be translated rapidly to the clinic. Citation Format: Marie-Eve Beaulieu, Toni Jauset, Daniel Masso-Valles, Jonathan Whitfield, Erika Serrano, Martin Montagne, Pierre Lavigne, Antonio Villaverde, Mireia Pesarrodona, Esther Vazquez, Laura Soucek. Preclinical validation of Myc inhibition by a new generation of Omomyc-based inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2645. doi:10.1158/1538-7445.AM2015-2645

Abstract 1085: MYC inhibition is a potent therapy against glioma and induces mitotic crisis in cancer cells.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Gliomas are the most common primary tumors affecting the adult human Central Nervous System (CNS). The most lethal is grade IV glioblastoma (GBM), which gives a median survival of only 15 months, but less severe grades also respond poorly to standard therapy. Myc is a bHLHZip transcription factor, causally implicated in most human tumors. In the past, we employed a dominant negative of Myc transactivation activity, termed Omomyc, and we showed that Myc inhibition is a potent strategy in cancer therapy, both in K-RasG12D-driven lung tumors and in T antigen-driven pancreatic β-cell insulinomas. Now, we make use of a mouse model of Ha-Ras driven glioma coupled with our Omomyc switchable model in order to assess Myc inhibition as a therapeutic strategy in glioma. Myc inhibition has a dramatic therapeutic impact in the animals, being able to both prevent formation and cause regression of tumors. We also tested neuroprogenitor cells derived from the same animal model as putative cells of origin of glioma. In this context, Myc inhibition reduced proliferation, increased death and impaired the self-renewal of Ha-Ras transformed neuroprogenitors. Similar results were obtained with human glioblastoma cell lines, which presented severe mitotic catastrophe as a consequence of Omomyc expression, revealing a new Achilles’ heel of glioblastoma. Finally, Myc inhibition was tested in orthotopic xenografts using patient-derived tumor samples and showed once again dramatic therapeutic impact, conferring a significant survival advantage to recipient animals. Conclusion: Myc inhibition is a potent therapeutic strategy in glioma and its effects include induction of mitotic crisis in tumor cells. Citation Format: Daniela Annibali, Jonathan R. Whitfield, Emilia Favuzzi, Toni Jauset, Erika serrano, Gerard Folch, Marta I. Cuartas, Alba Gonzalez, Lamorna Brown Swigart, Sergio Nasi, Gerard I. Evan, Joan Seoane, Laura Soucek. MYC inhibition is a potent therapy against glioma and induces mitotic crisis in cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1085. doi:10.1158/1538-7445.AM2013-1085

Abstract 4956: Pharmacological inhibition of Bruton's Tyrosine Kinase (BTK) as a therapy for insulinoma and pancreatic ductal adenocarcinoma.

Myc, a pleiotropic transcription factor that is deregulated and/or over-expressed in most human cancers, instructs multiple extracellular programs that are required to sustain the complex microenvironment needed for tumor maintenance, including remodeling of tumor stroma, angiogenesis and inflammation. We previously showed in a model of pancreatic [[Unsupported Character - Symbol Font β]] cell tumorigenesis that acute Myc activation in vivo triggers rapid recruitment of mast cells to the tumor site and that this is absolutely required for angiogenesis and macroscopic tumor expansion. Moreover, systemic inhibition of mast cell degranulation with sodium cromoglycate induced death of tumor and endothelial cells in established tumors. Hence, mast cells are required both to establish and to maintain the tumors. While this intimates that selective inhibition of mast cell function could be therapeutically efficacious, cromoglycate is not a practical drug for systemic delivery in humans and no other systemic inhibitor of mast cell degranulation has hitherto been available. Ibrutinib is a novel inhibitor of Bruton9s tyrosine kinase (Btk) that blocks mast cell degranulation and is currently in clinical trials as a therapy for B cell non-Hodgkin9s lymphoma. Here, we show that systemic treatment of insulinoma-bearing mice with Ibrutinib efficiently inhibits Btk, blocks mast cell degranulation and triggers collapse of tumor vasculature and tumor regression. We also show that pancreatic ductal adenocarcinoma (PDAC)-bearing mice treated with Ibrutinib survive longer and present reduced tumor stroma, suggesting that combinatorial therapy with Ibrutinib and standard of care is a feasible therapeutic approach. Conclusions: our data reinforce the notion that mast cell function is required for maintenance of certain tumor types and indicate that the Btk inhibitor Ibrutinib may be useful in treating pancreatic cancer. Citation Format: Daniel Masso-Valles, Erika Serrano, Jonathan R. Whitfield, Joseph J. Buggy, Nicole M. Sodir, Nesrine I. Affara, Lamorna Brown Swigart, Gerard I. Evan, Laura Soucek. Pharmacological inhibition of Bruton9s Tyrosine Kinase (BTK) as a therapy for insulinoma and pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4956. doi:10.1158/1538-7445.AM2013-4956