Evensen L.,University of Bergen |
Micklem D.R.,University of Bergen |
Micklem D.R.,BerGenBio |
Link W.,University of Bergen |
Lorens J.B.,University of Bergen
Cytometry Part A | Year: 2010
The successful progression to the clinic of angiogenesis inhibitors for cancer treatment has spurred interest in developing new classes of anti-angiogenic compounds. The resulting surge in available candidate therapeutics highlights the need for robust, high-throughput angiogenesis screening systems that adequately capture the complexity of new vessel formation while providing quantitative evaluation of the potency of these agents. Available in vitro angiogenesis assays are either cumbersome, impeding adaptation to high-throughput screening formats, or inadequately model the complex multistep process of new vessel formation. We therefore developed an organotypic endothelial-mural cell co-culture assay system that reflects several facets of angiogenesis while remaining compatible with high-throughput/high- content image screening. Co-culture of primary human endothelial cells (EC) and vascular smooth muscle cells (vSMC) results in assembly of a network of tubular endothelial structures enveloped with vascular basement membrane proteins, thus, comprising the three main components of blood vessels. Initially, EC are dependent on vSMC-derived VEGF and sensitive to clinical anti-angiogenic therapeutics. A subsequent phenotypic VEGFswitch renders EC networks resistant to anti-VEGF therapeutics, demarcating a mature vascular phenotype. Conversely, mature EC networks remain sensitive to vascular disrupting agents. Therefore, candidate anti-angiogenic compounds can be interrogated for their relative potency on immature and mature networks and classified as either vascular normalizing or vascular disrupting agents. Here, we demonstrate that the EC-vSMC co-culture assay represents a robust high-content imaging high-throughput screening system for identification of novel anti-angiogenic agents. A pilot highthroughput screening campaign was used to define informative imaging parameters and develop a follow-up dose-response scheme for hit characterization. High-throughput screening using the EC-vSMC co-culture assay establishes a new platform to screen for novel anti-angiogenic compounds for cancer therapy. © 2009 International Society for Advancement of Cytometry.
News Article | December 8, 2016
BERGEN, Norway--(BUSINESS WIRE)--Leading oncology biopharmaceutical company BerGenBio AS, today released important new preclinical study data on its first-in-class AXL inhibitor, BGB324 in another major disease indication. The study in breast cancer showed that AXL, a key factor in tumor resistance to the emerging class of new immune checkpoint inhibitors is effectively targeted through combination therapy with BGB324. The study data was presented in a poster today at the San Antonio Breast Cancer Symposium 2016. BGB324 is a highly selective small molecule inhibitor of the AXL receptor tyrosine kinase that is associated with poor overall survival in breast cancer. The new study “BGB324, a selective small molecule inhibitor of AXL tyrosine kinase, enhances immune checkpoint inhibitor efficacy in mammary adenocarcinoma” presented today in the Immunology and Preclinical Immunotherapy poster session, described a unique role for AXL in suppressing the anti-tumor immune response in breast cancer. AXL-targeting with BGB324 enhanced the effect of immune checkpoint blockade in aggressive mammary adenocarcinomas that display limited immunogenicity. The results showed that AXL-associated EMT and expression of immune suppressive cytokines increased in 4T1 tumors in response to immune therapy and correlated with a lack of response. The combination of BGB324 + anti-CTLA-4/anti-PD-1 resulted in durable primary tumor clearance and sustained tumor immunity in animals that rejected 4T1 tumor cell re-challenge. Importantly, the extensive metastasis to the lung, liver and spleen characteristic of this breast cancer model were concomitantly abrogated in the animals responding to the combination treatment. BGB324 enhanced tumor infiltration of effector cytotoxic T lymphocytes and NK cells while decreasing immune suppressive cell types. Notably, BGB324 showed direct effects on human M2 macrophages, reducing secretion of immune suppressive cytokines. Hence, selective inhibition of AXL signaling with BGB324 uniquely targets both tumor intrinsic and microenvironmental immune suppression mechanisms and increases checkpoint inhibitor efficacy. “We believe this strong new preclinical data again clearly demonstrates the rationale for combining BGB324 with immune checkpoint inhibitors to treat a wide range of aggressive cancers. AXL expression is increased in tumors in response to checkpoint inhibitor treatment and is an important resistance mechanism. Treatment with BGB2324 counters this and promotes the anti-tumor immune response. This supports our intention to combine the clinical-stage selective Axl inhibitor BGB324 with immune checkpoint inhibitors to improve treatment of human breast cancer.”
News Article | December 5, 2016
BERGEN, Norway--(BUSINESS WIRE)--Leading oncology biopharmaceutical company BerGenBio AS, today presented clinical and biological data from a Phase I trial of its potent, highly selective, first-in-class Axl inhibitor BGB324 in acute myeloid leukaemia in an oral session at the 58th ASH Annual Meeting & Exposition in San Diego. The company regards the results as an important indicator of the clinical utility of BGB324 in AML and the possibility of selecting patients who may benefit from treatment in advance of therapy. The oral presentation was entitled BGB324, an orally available selective Axl inhibitor exerts anti-leukaemic activity in the First-in-Patient trial BGBC003 and induces unique changes in biomarker profiles (Paper 0592, Session: Acute Myeloid Leukemia: Clinical Studies: New Drugs for Older AML). It reported clinical and biological data demonstrating the impact of BGB324 on the Axl signalling pathway in leukemic blast cells. Furthermore, an analysis of patients T-cell lymphocyte diversification illustrated that BGB324 amplified the immune response in a proportion of patients. Twenty-five patients (twenty-two with relapsed/refractory AML and three with high risk MDS) were treated in a classical 3+3 dose escalation design. Three dose levels were explored: 400/100 mg, 600/200 mg and 900/300 mg. Treatment was generally well-tolerated and steady-state levels of BGB324 were reached between three and six days after initiation of treatment. One AML patient achieved a CRi and two achieved a PR. Four additional AML patients (25%) experienced disease stabilisation for more than four months. One MDS patient experienced a PR. Treatment with BGB324 also led to an increase in the levels of soluble Axl receptor (sAXL) which was directly correlated to compound exposure (n=13; r=0.86), indicating that Axl could be used as a biomarker of target engagement. Professor Sonja Loges (MD, PhD), Principle Investigator for the Clinical Study commented: “BGB324 is active and well tolerated in AML patients, furthermore, BGB324 promotes diversification of the TCR repertoire in AML patients and therefore holds potential as an immune-activating drug.” Also presented was a poster that showed single cell signaling pharmacodynamics in a Phase 1 trial of BGB324 in acute myeloid leukemia (Paper 3995, Session: Acute Myeloid Leukemia: Clinical Studies: Poster III). The effect of BGB324 on intracellular signaling and the immune profile of leukaemic blasts in patients treated in the clinical study was investigated using phospho-flow cytometry. Leukemic blasts were identified using surface markers and treatment-related changes in direct and indirect downstream targets of Axl were explored. Analyses of blood samples from six patients showed rapid changes in signalling pathways downstream of Axl. In most patients, the CD117+/CD34- blast population appeared more responsive to treatment, and this cell population decreased during treatment with BGB324, suggesting that Axl inhibition may push leukemic blasts towards differentiation. The clinical trial is ongoing, and the signaling profile of leukaemic blasts in blood and bone marrow of treated patients will continue to be examined by conventional phospho-flow and mass cytometry. Richard Godfrey, Chief Executive Officer of BerGenBio, commented: “The two presentations show BGB324 is well tolerated in AML patients and exhibits anti-leukaemic activity. Furthermore, BGB324 can induce a diversification of the T-cell repertoire in AML patients and holds potential as an immune-activating drug. These studies suggest a patient enrichment strategy could be adopted to achieve a personalised medicine approach to BGB324 therapy.” BGB324 is a first-in-class, highly selective small molecule inhibitor of the Axl receptor tyrosine kinase. It blocks the epithelial-mesenchymal transition (EMT), which is a key driver in immune evasion, drug-resistance and metastasis. Phase Ib clinical trials are underway as single agent and in combination with standard of care drugs in acute myeloid leukaemia (AML) and erlotinib as well as docetaxel in non-small cell lung cancer (NSCLC). BGBC003 (NCT02488408) is a phase I/II multicenter open-label study of BGB324 as a single agent and in combination with cytarabine in patients with AML and high-risk MDS. The study consists of a dose-escalation phase of BGB324 and a single agent as well as combination with cytarabine arm at the recommended phase 2 dose. Primary endpoints of the trial are the evaluation of safety as well objective response rate and progression free survival. The study is run at centres in Norway, Germany and the US. For more information see: www.bergenbio.com/what-we-do/ongoing-clinical-trials/
Gjerdrum C.,University of Bergen |
Tiron C.,University of Bergen |
Hoiby T.,University of Bergen |
Stefansson I.,University of Bergen |
And 13 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010
Metastasis underlies the majority of cancer-related deaths. Thus, furthering our understanding of the molecular mechanisms that enable tumor cell dissemination is a vital health issue. Epithelial-to-mesenchymal transitions (EMTs) endow carcinoma cells with enhanced migratory and survival attributes that facilitate malignant progression. Characterization of EMT effectors is likely to yield new insights into metastasis and novel avenues for treatment. We show that the presence of the receptor tyrosine kinase Axl in primary breast cancers independently predicts strongly reduced overall patient survival, and that matched patient metastatic lesions show enhanced Axl expression. We demonstrate that Axl is strongly induced by EMT in immortalized mammary epithelial cells that establishes an autocrine signaling loop with its ligand, Gas6. Epiallelic RNA interference analysis in metastatic breast cancer cells delineated a distinct threshold of Axl expression for mesenchymal-like in vitro cell invasiveness and formation of tumors in foreign and tissue-engineered microenvironments in vivo. Importantly, in two different optical imaging-based experimental breast cancer models, Axl knockdown completely prevented the spread of highly metastatic breast carcinoma cells from the mammary gland to lymph nodes and several major organs and increased overall survival. These findings suggest that Axl represents a downstream effector of the tumor cell EMT that is required for breast cancer metastasis. Thus, the detection and targeted treatment of Axl-expressing tumors represents an important new therapeutic strategy for breast cancer.
News Article | November 10, 2016
WiseGuy Report's latest Pharmaceutical and Healthcare disease pipeline guide Pancreatic Ductal Adenocarcinoma – Pipeline Review, H2 2016, provides an overview of the Pancreatic Ductal Adenocarcinoma (Oncology) pipeline landscape. Pancreatic ductal adenocarcinoma is a malignant neoplasm that affects pancreas. Symptoms include upper abdominal pain that may radiate to back, yellowing of skin and the whites of eyes (jaundice), loss of appetite, weight loss, depression, blood clots. Predisposing factors include smoking, alcohol abuse, obesity, family history, age, chronic pancreatitis and diabetes. Treatment includes chemotherapy and radiation therapy. WiseGuy Report's Pharmaceutical and Healthcare latest pipeline guide Pancreatic Ductal Adenocarcinoma – Pipeline Review, H2 2016, provides comprehensive information on the therapeutics under development for Pancreatic Ductal Adenocarcinoma (Oncology), complete with analysis by stage of development, drug target, mechanism of action (MoA), route of administration (RoA) and molecule type. The guide covers the descriptive pharmacological action of the therapeutics, its complete research and development history and latest news and press releases. The Pancreatic Ductal Adenocarcinoma (Oncology) pipeline guide also reviews of key players involved in therapeutic development for Pancreatic Ductal Adenocarcinoma and features dormant and discontinued projects. The guide covers therapeutics under Development by Companies /Universities /Institutes, the molecules developed by Companies in Phase III, Phase II, Phase I, IND/CTA Filed and Preclinical stages are 4, 12, 15, 1 and 15 respectively for Similarly, the Universities portfolio in Phase II, Preclinical and Discovery stages comprises 1, 1 and 1 molecules, respectively for Pancreatic Ductal Adenocarcinoma. Pancreatic Ductal Adenocarcinoma (Oncology) pipeline guide helps in identifying and tracking emerging players in the market and their portfolios, enhances decision making capabilities and helps to create effective counter strategies to gain competitive advantage. The guide is built using data and information sourced from Global Markets Direct’s proprietary databases, company/university websites, clinical trial registries, conferences, SEC filings, investor presentations and featured press releases from company/university sites and industry-specific third party sources. Additionally, various dynamic tracking processes ensure that the most recent developments are captured on a real time basis. Note: Certain content / sections in the pipeline guide may be removed or altered based on the availability and relevance of data. - The pipeline guide provides a snapshot of the global therapeutic landscape of Pancreatic Ductal Adenocarcinoma (Oncology). - The pipeline guide reviews pipeline therapeutics for Pancreatic Ductal Adenocarcinoma (Oncology) by companies and universities/research institutes based on information derived from company and industry-specific sources. - The pipeline guide covers pipeline products based on several stages of development ranging from pre-registration till discovery and undisclosed stages. - The pipeline guide features descriptive drug profiles for the pipeline products which comprise, product description, descriptive licensing and collaboration details, R&D brief, MoA & other developmental activities. - The pipeline guide reviews key companies involved in Pancreatic Ductal Adenocarcinoma (Oncology) therapeutics and enlists all their major and minor projects. - The pipeline guide evaluates Pancreatic Ductal Adenocarcinoma (Oncology) therapeutics based on mechanism of action (MoA), drug target, route of administration (RoA) and molecule type. - The pipeline guide encapsulates all the dormant and discontinued pipeline projects. - The pipeline guide reviews latest news related to pipeline therapeutics for Pancreatic Ductal Adenocarcinoma (Oncology) - Procure strategically important competitor information, analysis, and insights to formulate effective R&D strategies. - Recognize emerging players with potentially strong product portfolio and create effective counter-strategies to gain competitive advantage. - Find and recognize significant and varied types of therapeutics under development for Pancreatic Ductal Adenocarcinoma (Oncology). - Classify potential new clients or partners in the target demographic. - Develop tactical initiatives by understanding the focus areas of leading companies. - Plan mergers and acquisitions meritoriously by identifying key players and it’s most promising pipeline therapeutics. - Formulate corrective measures for pipeline projects by understanding Pancreatic Ductal Adenocarcinoma (Oncology) pipeline depth and focus of Indication therapeutics. - Develop and design in-licensing and out-licensing strategies by identifying prospective partners with the most attractive projects to enhance and expand business potential and scope. - Adjust the therapeutic portfolio by recognizing discontinued projects and understand from the know-how what drove them from pipeline. Table of Contents 2 Introduction 5 Pancreatic Ductal Adenocarcinoma Overview 6 Therapeutics Development 7 Pancreatic Ductal Adenocarcinoma - Therapeutics under Development by Companies 9 Pancreatic Ductal Adenocarcinoma - Therapeutics under Investigation by Universities/Institutes 11 Pancreatic Ductal Adenocarcinoma - Pipeline Products Glance 12 Pancreatic Ductal Adenocarcinoma - Products under Development by Companies 15 Pancreatic Ductal Adenocarcinoma - Products under Investigation by Universities/Institutes 18 Pancreatic Ductal Adenocarcinoma - Companies Involved in Therapeutics Development 19 Pancreatic Ductal Adenocarcinoma - Therapeutics Assessment 52 Drug Profiles 65 Pancreatic Ductal Adenocarcinoma - Dormant Projects 234 Pancreatic Ductal Adenocarcinoma - Discontinued Products 235 Pancreatic Ductal Adenocarcinoma - Product Development Milestones 236 Appendix 243 List of Tables Number of Products under Development for Pancreatic Ductal Adenocarcinoma, H2 2016 13 Number of Products under Development for Pancreatic Ductal Adenocarcinoma - Comparative Analysis, H2 2016 14 Number of Products under Development by Companies, H2 2016 15 Number of Products under Development by Companies, H2 2016 (Contd..1) 16 Number of Products under Investigation by Universities/Institutes, H2 2016 17 Comparative Analysis by Late Stage Development, H2 2016 18 Comparative Analysis by Clinical Stage Development, H2 2016 19 Comparative Analysis by Early Stage Development, H2 2016 20 Products under Development by Companies, H2 2016 21 Products under Development by Companies, H2 2016 (Contd..1) 22 Products under Development by Companies, H2 2016 (Contd..2) 23 Products under Investigation by Universities/Institutes, H2 2016 24 Pancreatic Ductal Adenocarcinoma - Pipeline by BerGenBio AS, H2 2016 25 Pancreatic Ductal Adenocarcinoma - Pipeline by BioNTech AG, H2 2016 26 Continued….. List of Figures Number of Products under Development for Pancreatic Ductal Adenocarcinoma, H2 2016 13 Number of Products under Development for Pancreatic Ductal Adenocarcinoma - Comparative Analysis, H2 2016 14 Number of Products under Development by Companies, H2 2016 15 Number of Products under Investigation by Universities/Institutes, H2 2016 17 Comparative Analysis by Clinical Stage Development, H2 2016 19 Comparative Analysis by Early Stage Products, H2 2016 20 Assessment by Monotherapy Products, H2 2016 58 Number of Products by Top 10 Targets, H2 2016 60 Number of Products by Stage and Top 10 Targets, H2 2016 60 Number of Products by Top 10 Mechanism of Actions, H2 2016 63 Number of Products by Stage and Top 10 Mechanism of Actions, H2 2016 63 Number of Products by Routes of Administration, H2 2016 67 Number of Products by Stage and Routes of Administration, H2 2016 67 Number of Products by Top 10 Molecule Types, H2 2016 69 Number of Products by Stage and Top 10 Molecule Types, H2 2016 69 For more information or any query mail at [email protected] Wise Guy Reports is part of the Wise Guy Consultants Pvt. Ltd. and offers premium progressive statistical surveying, market research reports, analysis & forecast data for industries and governments around the globe. Wise Guy Reports understand how essential statistical surveying information is for your organization or association. Therefore, we have associated with the top publishers and research firms all specialized in specific domains, ensuring you will receive the most reliable and up to date research data available.
BerGenBio | Date: 2013-12-10
The invention relates to the control of gene expression. Specifically, the invention provides compositions and methods for the production and use of recombinant nucleic acid molecules that have the ability to specifically downregulate an expressed target gene in vivo. In some aspects, the invention provides methods for producing a hairpin DNA molecule where part of the molecule is derived from an mRNA that is a target for a small interfering RNA (siRNA) derived from the hairpin. In other aspects, the invention provides synthetic hairpin adapter oligonucleotides that are used in the construction of siRNA-producing cassettes. In other aspects, the invention provides methods for testing for the presence or absence of specific inhibitory activity of an RNAi trigger molecule, and in still other aspects, the invention provides methods for identifying an active RNAi trigger molecule from a library of RNAi trigger molecules. In still other aspects, the invention provides methods for identifying a polynucleotide from a plurality of candidate target polynucleotides that is specifically targeted by an RNAi trigger molecule. In other aspects, the invention provides epi-allelic series of hypomorphic RNAi trigger molecules specific for any gene of interest, where the series of RNAi trigger molecules have a variety of uses including analysis of gene function and drug target development.
BerGenBio | Date: 2014-11-28
The invention provides a compound for use for treating, preventing or managing a condition associated with the activation, mutation and/or over-expression of one or more kinases, wherein if the condition is associated with Axl over-expression, it is also associated with the activation, mutation and/or over-expression of one or more other kinases, and wherein the compound has a structure according to formula (I) : wherein the symbols used in formula (I) are as defined herein.
BerGenBio | Date: 2013-05-02
The use of Akt3 as a biomarker for detecting the occurrence of epithelial-to-mesenchymal transition (EMT) in a subject, and the use of Akt3 inhibitors to treat cancer is disclosed herein. Also disclosed are various methods for detecting the occurrence of epithelial-to-mesenchymal transition (EMT) in a subject by measuring Akt3 expression and/or activity.
News Article | February 7, 2014
Backers included new and existing investors (Sarsia Seed AS and Investinor AS). The company intends to use the funds for the development of its portfolio of innovative cancer therapeutics. Led by Richard Godfrey, CEO, BerGenBio is developing BGB324, a selective Axl kinase inhibitor, which is currently in Phase Ib clinical studies to evaluate its safety and initial signs of efficacy to treat different cancers as a single agent and in combination with other drugs. The company’s pipeline programs also include BGB001 and BGB002, which are at different stages of preclinical development.