Lymphomas
Inhibition of cell death in the pathogenesis of lymphomas
Inhibition of cell death including apoptosis is a crucial step early in the pathogenesis of lymphomas because a) dividing non-neoplastic lymphocytes have a limited lifetime and die via apoptosis and b) neoplastic cells accumulate genetic aberrations including oncogene activations that in normal cells result in stress-induced apoptosis.
Inhibition of cell death is not only important in the development of lymphomas but is also a major factor causing intrinsic resistance of tumor cells to chemotherapy in chemotherapy-refractory patients. Identifying the cell death inhibiting mechanisms in these lymphomas may allow the development of specific strategies that neutralize these mechanisms and tailoring therapy. Our research is focused on
- identification of defects in cell death pathways in Non-Hodgkin lymphomas
- understanding of the mechanisms causing resistance to cell death and investigation whether these cell death inhibiting mechanisms are related to a poor clinical response to chemotherapy
- determination of optimal strategies to kill lymphoma cells by targeting specific apoptosis inhibiting molecules or by triggering alternative pathways of cell death
- predefinition of patients that will benefit of a specific therapy
- predefinition of lymphomas or precursor cells which will transform to a (more aggressive) lymphoma
Diffuse large B-cell lymphoma (DLBCL)
DLBCL is the most frequent type of non-Hodgkin Lymphoma in adults. Treatment has been based on R-CHOP for years resulting in a 5-year survival of 30-80% and 50% long-term survival. From a biological point of view, DLBCL is a heterogeneous group of diseases in which several different oncogenetic pathways play a role. Information on genetic and epigenetic alterations may be used for refined classification, but increasingly so as potential tools for treatment stratification. Gene expression profiling (GEP) studies have revealed a major dichotomy in germinal center B-cell like (GCB) and activated B-cell like (ABC). Both classes are characterized by various molecular alterations that are enriched, but not unique to these classes. Moreover, next-generation sequencing results revealed also classes of alterations that are relatively independent on the GCB/ABC dichotomy. The availability of newly developed compounds brings targeted treatment based on the specific driving alterations in DLBCL within reach. It is the aim to launch a clinical trial with a Bayesian randomized design for targeted treatment in DLBCL by HOVON within 3 years.
Follicular lymphoma (FL)
FL is the prototypical indolent B-cell lymphoma and thereby a model for a larger group of lymphoid diseases. Little is known about the early phases of oncogenesis in FL and early interactions between B-cells and their immune microenvironment
We focus our research on
- the development of a molecular diagnostic tool for differential diagnosis of DLBCL and BL
- the development of tools for targeted treatment in DLBCL
- understanding of the oncogenesis of subtypes of DLBCL
Staff
Saskia Cillessen PhD - staff member
Daphne de Jong MD PhD - staff member
Chris Meijer MD PhD - staff member
Matthias Mendeville - PhD student
L. de Baaij - PhD student
M. Radersma - PhD student
J. van de Water - PhD student