| Project Detail |
Glioblastoma is one of the most difficult tumors to treat, notorious for its resistance to treatment, despite recent advances in the understanding of the evolution of the (epi-)genetic landscape during progression and escape from treatment. The failures of single agent therapies tested in clinical trials have added to the pressure to develop rational combination therapies. However, the rational choice for successful combination therapy remains a challenge. We aim at identifying druggable vulnerabilities of cancer relevant pathways revealed upon disturbing the tumor cells by Bromodomain inhibitors (BETi). BET inhibitors are a new class of drugs that act on Bromodomain and extra-terminal (BET) family proteins, such as BRD4, which are important regulators of enhancers of cancer relevant genes. In the present project, we aim at elucidating underlying mechanisms relevant for the biology of BETi (a) for genes downregulated by BETi, likely to be direct targets, and indicating a subgroup of patients who may potentialy profit from treatment and (b) genes upregulated by BETi that may activate rescue pathways conferring resistance. For both, we aim at finding the appropriate second drug. This will be followed by testing the specificity of the observed effects using genetic interference, to test the hypothesized mechanism(s), such as inducible shRNA constructs, inducible gene expression vectors. Finally, the potential clinical relevance of the finding, and the identified treatment combination will be tested in patient derived orthotopic GBM xenografts, followed non-invasively using magnetic resonance imaging and spectroscopy in collaboration with the CIBM/EPFL. Respective biomarkers will be developed that can be tested in window of opportunity studies in mouse orthotopic glioma models, with the aim to translate into respective studies in patients. We have shown the feasibility of our approach in a proof of principle study. The present project will provide the basis for the crucial next steps for testing innovative combination treatments. Taken together, may not only uncover potentially druggable pathways/targets, but may in addition provide tools for in vivo monitoring of treatment response that eventually can be translated into the human setting.In a more exploratory part we will investigate the concerted BETi-mediated downregulation of a tumor stem-cell related, HOX-gene dominated signature. Expression of this signature has previously been associated with worse outcome in glioblastoma patients, however, little is known about the mechanism of the tumor associated activation of the signature. Building on preliminary results of the (epi)genetic landscape of the HOX A region in GBM and respective, derived sphere lines, we aim at uncovering underlying mechanisms, by investigating the associated chromatin marks and chromatin conformation and compare between GBM sphere lines with high HOX signature expression and those without. Finaly we propose a translational study aiming at establishing the clinical value of MGMT methylation in a clinical trial for IDHmt low grade glioma (LGG) treating patients with TMZ or radiotherapy. While the MGMT methylation status is well established as predictive factor benefit from TMZ treatment for GBM, this clinical value is not established for LGG. We will propose a cut-off to predict benefit from TMZ, and will validate it second part of the cohort. This may provide a tool for de-escalation of treatment, to delay late toxicity and preserve cognitive function, and quality of life. |
