Abstract
Hematologic malignancies are cancers that primarily affect the blood, bone marrow and lymph nodes. Among the different subtypes, B-cell non-Hodgkin lymphoma (B-NHL) and Acute Myeloid Leukemia (AML) are the most prevalent indications. Common to both indications, alterations in the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway are frequently observed, leading to constitutive activation and oncogenic signalling. Known key effectors within the pathway such as Bruton's tyrosine kinase (BTK), interleukin-1 receptor associated kinases (IRAKs), Myeloid differentiation primary response 88 (MYD88), and Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) represent promising therapeutic targets for these indications and have been at the center of significant drug discovery efforts. In order to tackle common limitations associated to canonical small molecule inhibitors (SMI) (e.g., resistance mutations, lack of response due to scaffolding functions, …), this project is aimed at exploring the therapeutic potential of selective target degradation through PROteolysis-TArgeting Chimera (PROTAC). PROTAC represents an innovative protein degradation technology able to induce protein degradation by taking advantage of the ubiquitin proteasome pathway. The goal of the project is to provide a better understanding of the therapeutic potential of PROTACs specific for BTK, IRAK1 and IRAK4 in comparison to their respective SMI counterparts. To this end, we will evaluate the molecular and functional consequence of target degradation or inhibition in relevant models of AML and B-NHL as well as reflect the work on AML primary patient material. In addition, potential synergistic activity between PROTACs and clinically relevant SOC/SMIs options will be evaluated. Last, potential on-target/off-tumor activity in immune cell sub-types in which the NF-kB pathway is known to play a role (e.g., T-cells) will be evaluated.
Researcher(s)
Research team(s)
Project type(s)