< Back to previous page

Project

Preclinical evaluation of withaferin A chemosensitisation in GC therapy resistant B- and T-cell haematological malignancies.

Glucocorticoids (GCs) have been employed as a conventional treatment option for various haematological diseases, including acute lymphoblastic leukaemia (ALL), chronic lymphoblastic leukaemia (CLL), multiple myeloma (MM), Hodgkin and non-Hodgkin lymphomas. These malignancies affecting children, young adults and the elderly, are all characterized by the abnormal growth of cells from the myeloid or lymphoid lineage. Despite the use of GCs as potential anti-cancer drugs, some tumours are not responsive to these drugs (primary resistance) and those which do respond develop resistance during therapy (acquired resistance). As such, the majority of patients relapse, develop resistance, or eventually might die from the disease within 5-10 years of initial diagnosis. The molecular basis of GC resistance is still poorly understood, although emerging evidence supports an important etiologic role for rewiring of cell death kinase signalling pathways. As such there is an urgent need to develop novel and better chemosensitising combination therapies with less adverse side effects. In addition, precise clinical staging and accurate identification of high-risk patients is important to determine GC therapy response, subsequent prognosis and allocate tailored (combination) treatment to each individual patient. We have identified Withaferin A (WA) as a top prioritized anti-cancer chemosensitizing compound for further (pre)clinical evaluation in GC resistant multiple myeloma and B- and T-cell leukemias. However, despite its promising chemosensitizing properties in vitro, preclinical validation in vivo is limited, due to lack of established mouse models for haematological malignancies. Moreover, commercial interest in preclinical studies with WA is lacking, since natural products can not be patented or since purification and/or full stereoselective synthesis of complex natural molecules can be problematic for translational biomedical applications. Based on our promising preliminar findings, chemosensitisation of GC resistant leukemia, lymphoma and myeloma cells by Withaferin A will be preclinically evaluated in different in vitro (cell models) and in vivo (genetically engineered mouse models and patient derived xenografts in immunedeficient animals) model systems. Furthermore, by using a novel innovative kinase peptide array platform, we will be able to establish a phosphopeptide fingerprint of kinome perturbations associated with GC resistance and/or chemosensitisation by WA in in vitro/in vivo samples as well as ex vivo patient samples. This phosphopeptide fingerprint will be applied as a diagnostic and/or predictive tool for personalized patient centered therapeutic applications (patient stratification) in treatment of poor prognosis GC resistant haematological malignancies.
Date:1 Oct 2018 →  30 Sep 2022
Keywords:CHEMOTHERAPEUTICS
Disciplines:Biomaterials engineering, Biological system engineering, Biomechanical engineering, Other (bio)medical engineering, Environmental engineering and biotechnology, Industrial biotechnology, Other biotechnology, bio-engineering and biosystem engineering
Project type:Collaboration project