Project description
Organoids for lymphoma drug screening
Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma that is categorised into two subtypes: activated B cell-like (ABC) and germinal centre B cell-like (GCB) DLBCL. ABC DLBCL is often unresponsive or resistant to the first line of treatment, necessitating alternative solutions. The EU-funded LOISE project is working under the hypothesis that the lymph node microenvironment plays a key role in treatment response. Therefore, the project aims to generate ex vivo organoids that recapitulate the infiltration of T helper cells and the activation of extracellular matrix-mediated pathways that characterise the native microenvironment. These organoids will help researchers understand the microenvironment features that influence the outcome of novel inhibitors.
Objective
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL) in Europe and worldwide with more than 463/100 000/year. Activated B cell (ABC)-DLBCL represents the more aggressive and chemo-resistant subtype to the frontline therapy Rituximab (R)-CHOP (doxorubicin, vincristine, prednisone, mechlorethamine) with 40% of patients experiencing no response or relapse. Therefore, new treatments are needed to improve the clinical outcome of ABC-DLBCLs. A newly defined characteristic feature of the ABC-DLBCL subtype is the concurrent constitutive activation of B cell receptor (BCR) and Toll-like receptor (TLR) pathways that result in the upregulation of the NF-ĸB through cooperative signaling. In ABC-DLBCLs the NF-ĸB signal is mediated from the downstream regulator Mucosa-associated lymphoid tissue lymphoma translocation protein 1(MALT1) paracaspase that is upregulated in 70% of these tumors.. For this reason, MALT1 paracaspase has become an attractive therapeutic target and MALT1 inhibitors have been developed.. However, previous studies indicate that approximately 63% of patients respond to BCR pathway inhibitors, and therefore understanding factors such as the intricate survival signals imparted by the lymph node tumor microenvironment (LymphTME) in ABC-DLBCL is critical for clinical translation of MALT1 inhibitors. Two key elements of the LymphTME are the infiltration of T helper cell (Th) and the activation of ECM mediated pathways. The Aim of LOISE project is to establish an ex vivo organoids that will mimic the T immunological synapse and ECM features with the purpose to elucidate their role on ABC-DLBCL survival and signaling response to BCR pathway inhibitors. These organoids will be used to designed a combinatorial targeted therapy for ABC-DLBCL.
Fields of science
Programme(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Funding Scheme
HORIZON-AG-UN - HORIZON Unit GrantCoordinator
72074 Tuebingen
Germany