June 3, Bergen, Norway – BerGenBio AS, an emerging oncology biopharma company, has presented data on the importance of the receptor tyrosine kinase, Axl, in acute myeloid leukemia (AML) at the ASCO Annual Meeting 2013, in Chicago, IL. The research, completed by a team led by Dr Sonja Loges from the University Hospital Hamburg-Eppendorf, suggests that Axl represents a novel prognostic marker and potential therapeutic target in AML.
As very few novel AML drugs have been approved in the past 20 years, there is an urgent need to identify novel targets and therapeutic strategies to treat underserved AML patients. Axl is a member of the TAM family of receptor tyrosine kinases (TAMRs) together with Sky or Tyro3 and Mer. Members of the TAMR family are abundantly expressed in physiological and malignant hematopoiesis. Axl, the receptor for Growth Arrest-specific protein 6 (Gas6) has been found to play a role in AML pathobiology and therapy resistance. Furthermore, Axl expression confers worse prognosis to AML patients. Gas6 exerts pleiotropic effects in pathobiology and promotes proliferation and survival of different cancer cell lines in vitro.
The study showed higher expression of Axl in AML bone marrow BM and that BerGenBio’s Axl inhibitor BGB324 dose-dependently inhibited proliferation of primary AML cells. Sensitivity towards BGB324 correlated with Axl expression on leukemia cells. Combination therapy with BGB324 and cytarabine exerted an additive therapeutic effect and BGB324 was found to chemosensitize cytarabine-resistant AML cells. Analyses revealed that Gas6 expression was low in AML cells, similar to healthy hematopoietic cells, while it was abundantly expressed in AML BM stromal cells with fibroblastic/mesenchymal morphology (BMDSCs). Gas6 expression was considerably lower in control BMDSCs, suggesting a possible paracrine interaction between AML cells and BMDSCs leading to Gas6 upregulation in the stroma compartment. The interaction between stroma-derived Gas6 and Axl+ leukemia cells forms a chemoprotective niche for leukemia cells. In line with these findings Axl blockade chemosensitizes Mv4-11 cells for treatment with doxorubicine in vivo.
Richard Godfrey, CEO of BerGenBio, added “Dr. Loges’s work has built up a compelling picture of the key role that Axl and its signaling pathway play in AML pathobiology in forming a chemoprotective niche, presenting a promising therapeutic target in AML. The results demonstrate that Axl inhibition by BGB324 has the potential to treat chemosensitive and chemoresistant AML.”
Category: Leukemia, Myelodysplasia, and Transplantation
Title: Use of Axl, a therapeutic target in AML, to mediate stroma-induced chemoresistance
Meeting: 2013 ASCO Annual Meeting
Session: Sat, Jun 1 8:00 AM – 12:00 PM
Abstract No: 7027
Citation: J Clin Oncol 31, 2013 (suppl; abstr 7027)
Author(s): Isabel Ben Batalla, Alexander Schultze, Mark Wroblewski, Robert Erdmann, Michael Heuser, Kristoffer Riecken, Mascha Binder, Miguel Cubas-Cordova, Janning Melanie, Jasmin Wellbrock, Boris Fehse, Christian Hagel, Jürgen Krauter, James B. Lorens, Arnold Ganser, Walter M. Fiedler, Peter Carmeliet, Klaus Pantel, Carsten Bokemeyer, Sonja Loges; II. Medical Clinic & Institute of Tumor Biology, Campus Forschung, University Hospital Hamburg-Eppendorf, Hamburg, Germany; Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany; Research Department Cell and Gene Therapy, Campus Forschung, University Hospital Hamburg-Eppendorf, Hamburg, Germany; II. Medical Clinic, Campus Forschung, University Hospital Hamburg-Eppendorf, Hamburg, Germany; Department of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; The Department of Biomedicine, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway; Katholieke Universiteit Leuven, Leuven, Belgium; Institute of Tumor Biology, Campus Forschung, University Hospital Hamburg-Eppendorf, Hamburg, Germany
About BerGenBio AS
BerGenBio AS is a biopharmaceutical company located in Bergen, Norway. The company is committed to developing first in class therapeutics inhibiting EMT and the formation of cancer stem cells and preventing or reversing mechanisms of drug resistance. BerGenBio has a deep understanding of cancer biology, and in particular the tumor micro-environment, biomarkers and novel cancer treatments. The company is founded on proprietary platform technology called CellSelect™, which uses information from RNAi screening studies to identify and validate novel drug targets and biomarkers.