[Webinaire] [EN] How to better predict your drug efficacy to combat liver diseases? Sensitive pre-clinical models to understand mechanism of action to design novel & successful therapies

[Webinar] How to better predict your drug efficacy to combat liver diseases?

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Samira Benhamouche-Trouillet, PhD, Senior Study Director
2 Juillet 2020
17h CEST


Liver pathologies account for significant burden of disease and costs, with more than 800 million people affected and a mortality rate of approximately 2 million deaths per year worldwide. Given the prevalence of obesity and diabetes mellitus worldwide, NAFLD will increasingly become the leading cause of chronic liver disease and hepatocellular carcinoma. For now, liver transplantation remains the only effective therapeutic option.

Acute liver injury is a syndrome of severe and abrupt hepatocyte injury and inflammation leading to liver failure. Many different etiologies have been identified, with acetaminophen (APAP) overdose and viral hepatitis being the most common causes. Chronic Liver diseases (CLD), irrespective of the etiology, are characterized by parenchymal injury, activation of inflammatory response, angiogenesis and sustained activation of liver fibrogenesis. Liver cirrhosis represent an advanced stage of CLD characterized by the formation of fibrotic septa surrounding regenerative nodules, changes in vascular architecture, portal hypertension and complications such as liver failure and hepatocellular carcinoma (HCC).

Providing palliative and curative solutions is an urgent necessity. At Oncodesign, we offer and develop both complementary and integrated strategies to mimic the different steps of liver diseases and cancer progression in mouse models, in order to develop novel therapies and elucidate the mechanisms of action. 

Key learning objectives

  • Introduction to liver pathogeneses
  • Models of acute liver injury
  • Models of liver fibrosis and NASH
  • Models of liver cancer

Discover our speaker Samira Benhamouche-Trouillet 

Samira Benhamouche-Trouillet is a study director at Oncodesign in the department of in vivo pharmacology.
She received her PhD in 2008 in biochemistry, cellular and molecular biology from Paris 11 University and Cochin institute (Paris, France) where she studied the role of Wnt/b-catenin signaling in liver homeostasis, regeneration and carcinogenesis. Then, for her postdoctoral training, she joined the Massachusetts General Hospital Cancer Center/ Harvard medical School (Boston, USA) from 2008 to 2013 to study the role of hepatic progenitor cells in cancer and mechanisms of biliary cells polarization and lumen formation during liver development. From 2013 to 2018, she was a group leader and assistant professor at Bordeaux University and Centre-Hepato-Biliaire (Paris area) where she worked on signal transduction pathways involved in lipid and glucose metabolism, NASH pathogenesis and in liver regeneration. In September 2018, she joined Oncodesign where she has been developing preclinical models for liver diseases and manages proof-of concept studies in inflammatory diseases and oncology.

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[Webinaire] [EN] NEW INTERACTIVE PANEL WEBINAR] DRIVE™: Brothers in Arms to support small molecule drug discovery from Hit to IND

Enregistrement en ligne  [Webinar] [NEW INTERACTIVE PANEL WEBINAR] DRIVE™ : Brothers in Arms to support small molecule drug discovery from Hit to INDEnregistrement en ligne  [Webinar] [NEW INTERACTIVE PANEL WEBINAR] DRIVE™ : Brothers in Arms to support small molecule drug discovery from Hit to IND

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7 Juillet 2020
17h CEST


Outsourcing drug discovery has become an overwhelmingly accepted approaches across the pharmaceutical industry from virtual biotech to large pharmaceutical companies as part of the globalization process. It does represent a cost-effective opportunity to access specialized technologies and expert scientist resources having a broad knowledge of pharmaceutical drug discovery development. Oncodesign’s objective with DRIVE™ offer is to provide its customers with the best possible options and state-of-the-art technologies to progress their drug discovery in the shortest possible time with the highest quality.

Oncodesign is doing so by setting up under a single leadership, privileged partnering with selected and trusted companies sharing the same values of innovation and quality as its own. 
Hits finding and validation are important phases in early drug discovery. With Program, Oncodesign is providing DNA encoded libraries, fragments screening along with Hit validation using NanoDSF, MST, SPR, ITC and Structural Biology (Cryo-EM and X-Ray crystallography) supported by artificial intelligence. 

Key learning Objectives

  • Introduction to a solution provider from hits finding to IND filing
  • Advantages of drug discovery integrated provider vs silos approach
  • Special focus on Hit identification and validation across DNA encoded libraries, Artificial Intelligence, Biophsysics and Biostructures  

Discover our speakers

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L’évaluation de l’immunothérapie du cancer nécessite l’utilisation de modèles animaux précliniques appropriés reflétant suffisamment la situation physiologique chez l’homme.

[Congrès] [EN] AACR Virtual Meeting II – 22 -24 Juin 2020

AACR Virtual Meeting II – 22 -24 June

The AACR Annual Meeting program covers the latest discoveries across the spectrum of cancer research—from population science and prevention; to cancer biology, translational, and clinical studies; to survivorship and advocacy—and highlights the work of the best minds in research and medicine from institutions all over the world.

Modelling the liver diseases from chronic inflammation injury to hepatocellular carcinoma for development of new liver treatments | Abstract #5638

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I read the abstract below

Introduction: Anemia is a condition characterized by low Hemoglobin levels. Anemia is observed during tumor development through the release of inflammatory cytokines, which will affect iron availability, a key component of red blood cells. In recent years, consequences of anemia of cancer on patients is getting growing recognition from a quality of life perspective, as well as its impact on the treatment scheme and hospitalization duration. Cancer-induced anemia has been identified in 30% of treatment-naive cancers (ECAS study, 2011 – WHO methodology). The proportion of anaemic patients reaches 70% following treatments, such as chemotherapies. Current approaches consider erythropoietin derivatives, formulated iron or transfusions, which does not address underlying chronic inflammation. Moreover, their use is limited as a consequence of toxicities (EPO, formulated iron) or availability (transfusion).
Increased expression of Hepcidin, a peptidic hormone regulating the storage of bioavailable iron, has been demonstrated as downstream effector of key inflammatory cytokines activation of ALK2/Smad axis. ALK2 (Activin-like receptor kinase 2) plays a critical role in the Smad signaling pathway and the production haemoglobin, through the regulation Hepcidin production in the liver. As a consequence, the selective inhibition of ALK2 as emerged as a valuable target for the treatment of Hepcidin-driven anemia of cancer to provide an alternative to current treatments.
Results: OD52, a potent and selective macrocyclic ALK2 inhibitor identified from Nanocyclix® technology platform, was used as in vitro pharmacological tool to investigate the impact of ALK2 inhibition on Hepcidin expression level in HepG2 cells, as well as in mice hepatocytes. BMP6-induced expression of Hepcidin mRNA was completely inhibited by LDN-193189 to low detectable levels, whereas OD52 normalized its expression. Further validation was performed in mice hepatocytes, where OD52 decreased Hepcidin expression to a lower extend as compared with LDN-193189. These experiments confirmed the importance of selectivity within BMP-kinase receptor family, where ALK3 component represents an undesired off-target.
In vivo evaluation of the compound in the acute model of turpentine-induced anemia demonstrated a normalization of haemoglobin level. In contrast, LDN-193189 increased haemoglobin above vehicle group to a level mimicking hemochromatosis, likely due to its ALK3 component.
Through further medicinal chemistry optimization, OD66 was identified as suitable in vivo pharmacological tool and was evaluated in a cancer-induced anemia mouse model. The compound demonstrated a normalization of haemoglobin levels to comparable levels with the tumor-free group without displaying toxicity.
Conclusion:  The identification of potent and selective Nanocyclix® ALK2 inhibitors and their evaluation in relevant in vitro and in vivo models demonstrated a normalization of haemoglobin levels through the modulation of Hepcidin expression. This collaborative work warrants further optimization towards the identification of a preclinical candidate.

Macrocyclic ALK2 inhibitors as potential anemia of cancer treatment | Abstract #4028

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I read the abstract below

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death and accounts for >80% of primary liver cancer worldwide. Early stage HCC can be treated by local ablation, surgical resection or liver transplantation. Systemic pharmacological options are limited and only a few available (kinase and immune-checkpoint inhibitors). Most cases of liver cancer occur in the setting of chronic liver diseases. Risk factors include chronic Hepatitis B and C, alcohol addiction and metabolic diseases. HCC is a multistep process comprising chronic liver injury, inflammation, fibrosis/cirrhosis and cancer formation. Therefore, providing palliative and curative options remains a high medical need.
In order to better evaluate new preventive and curative treatments of liver cancers we developed complementary and integrated strategies to mimic the liver cancer initiation and progression steps in mouse models. These models involve chemotoxic agents, diet-induced disorders and implantation strategies.
We first established an orthotopic syngeneic model using Hepa1.6 mouse liver hepatoma cells. Hepa1.6-derived tumor growth was characterized through liver index, alpha-fetoprotein measurement in serum and liver, and MRI. The response to chemotherapy (Sorafenib) and immunotherapy (anti PD-1) was also assessed. Moreover, a panel of Patient-Derived Xenograft models (PDXs) are available to assess new treatment options in human HCC with regards of the genetic mutations and the variety of etiologies seen in human.
During the course of HCC formation, the liver undergoes cycles of inflammation, necrosis with regeneration, fibrosis, cell dysplasia and ultimately HCC. Thus, we developed two models of non- alcoholic steato-hepatitis (NASH); The first model involves chronic administration of hepatotoxic CCL4 associated with a high-fat and high-fructose diet. Mice develop steatohepatitis and fibrosis within 4 to 8 weeks as assessed with biochemistry parameters (AST, ALT…), gene expression levels of inflammatory and fibrotic genes as well as histological scores and MRI. The effect of obeticholic acid was successfully evaluated in this model. The second model is the STAM model induced by a low dose of Streptozotocin and high fat diet regimen. In this model, mice develop metabolic syndrome (increased body weight gain, hyperglycemia and hyperlipidemia), NASH (steatosis, inflammation, fibrosis) within 12 weeks and HCC within 16 weeks. The responses to standard of care and to immunotherapy together with the characterization of the immune cell populations are currently under investigation.
Altogether, these results demonstrate the usefulness of this liver diseases development program to discover and identify new treatments that could circumvent the progression of liver cancer.

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[Webinaire] [EN] How to assess the interplay between tumor, microbiota and therapies? A comprehensive platform to investigate bacteria as immuno-modulating vectors or agents.

 [Webinar] How to assess the interplay between tumor, microbiota and therapies? A comprehensive platform to investigate bacteria as immuno-modulating vectors or agents.

Voir la présentation en ligne [Webinar] How to assess the interplay between tumor, microbiota and therapies? A comprehensive platform to investigate bacteria as immuno-modulating vectors or agents.

Sylvie Maubant, PhD, Study Director
25 Juin 2020
17h CEST


A comprehensive platform to investigate bacteria as immuno-modulating vectors or agents.
Preclinical and clinical studies have shed light on the beneficial role of bacteria for cancer therapy. Indeed, these works have demonstrated that these microorganisms have properties that allow them to selectively colonize tumor tissue and that they could also be considered as predictive drug efficacy biomarkers. Based on these results, bacteria are now used 1) for delivering therapeutic proteins into tumor cells or antigens into body, 2) for shaping gut microbiota.
Ultimately these approaches lead to the activation of an immune response against the tumor. Owing to our scientific and technological expertise at manipulating microbes, Oncodesign proposes tailor-made strategies to clients for investigating the efficacy of their bacteria-based treatments and/or the effect of their therapies on microbiota in vitro and in vivo.

Key learning objectives

  • Introduction to bacteria-mediated cancer therapy.
  • How can Oncodesign support your evaluation of bacterial therapies and/or the impact of your treatments on microbiota?
  • Case study examples

Discover our speaker Sylvie Maubant

Sylvie Maubant has more than 15 years of experience in preclinical research in oncology field.
She obtained a Ph.D in Biology, Medicine and Health from the University of Caen in France then she continued her career as a postdoctoral researcher at several institutes to work on projects related to the identification of new therapeutic targets, drug development and/or validation of therapeutic tools in collaboration with industry. In 2014, Sylvie joined Oncodesign in vivo department as a study director.
Since 2018, she has been mainly involved in bacteria-oriented programs for clients

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L’évaluation de l’immunothérapie du cancer nécessite l’utilisation de modèles animaux précliniques appropriés reflétant suffisamment la situation physiologique chez l’homme.