Vrije Universiteit Brussel

 

Multiple Myeloma Research

Multiple myeloma (MM) represents a malignant B cell disorder, characterized by an accumulation of monoclonal plasma cells in the bone marrow (BM). It accounts for approximately 1 % of all malignant diseases and represents about 10% of all hematological malignancies. The median age at diagnosis is 65 years and about 3% of patients are younger than 40 years.


The cause of MM is unknown. Environmental exposures that may increase the risk of MM include high doses of ionizing radiation and occupational exposure in the farming and petrochemical industries.


The clinical presentation of MM varies from totally asymptomatic in patients whose disease is discovered incidentally to life-threatening clinical events. The tumor itself, and the host response to it result in organ dysfunction with a variety of symptoms. These include bone pain with or without associated fractures (due to osteolysis), anemia, susceptibility to infections and hypercalcemia, with or without renal failure caused by the precipitation of monoclonal light chains in the collecting tubules.


The hallmark of MM is the detection of an M-protein in blood and/or urine (Bence Jones). Serum protein electrophoresis reveals a band in 80% of patients. The remaining 20% of patients will have either hypogammaglobulenimia or a normal appearing pattern. In this patient population with oligo- or non-secretory MM, the serum free light-chain assay can be useful for monitoring.


The research work in the department of Hematology-Immunology relates to different aspects in the biology and treatment of MM, using both human MM cells and the murine 5TMM model. The latter is a syngenic immunocompetent murine model, which mimics the human disease closely. The research group focuses, in particular on interactions between MM cells and their host microenvironment and studies how specific interactions with endothelial cells, osteoclasts and stromal cells can be targeted for therapeutical intervention, with special emphasis on overcoming drug-resistance.
MM develops in the BM where the tumor cells receive growth and survival signals. The MM cells adhere to BM stromal cells through integrins. The BM stromal cells can induce drug resistance in the MM cells. This drug resistance is called “cell-adhesion mediated drug resistance” or CAM-DR. Several CAM-DR mechanisms have been described such as inhibition of apoptosis and desensitization towards medication. Which are the most important CAM-DR mechanisms is still unclear. We are currently investigating how CAM-DR occurs in the 5TMM model and how we can inhibit it. We are testing several integrin inhibitors in combination with bortezomib and examining their therapeutic effects.

A new form of MM treatment is immune therapy. Hereby, the immune system of the cancer patients is activated against the cancer cells. However, the immune system is often disturbed in these patients. We want to investigate the function of a specific T cell namely the “natural killer” NKT cell and see if we can activate this T cell against the MM cells. NKT cells can be divided in iNKTs or type I NKTs and type 2 NKTs. iNKTs are characterized by an invariant chain, namely TCRValpha 24 (human) or TCRValpha14 (mouse) and can be activated by alpha-galactosylceramide. We are investigating the function and number of iNKTs in both the 5TMM model and in MM patients (compared to healthy volunteers). We will examine if we can reactivate the iNKTs in the mice and prolong their survival. We will also investigate the effects of Lenalidomide (LEN) on the NKT cells. LEN is a drug which is currently used as treatment in MM and has known immunomodulating functions.

As mentioned above, the local BM microenvironment is critical for supporting MM cell survival, proliferation, growth and development of drug resistance. New drugs have been identified which target both MM cells and cells of the BM environment. Treatment of MM consists of older drugs like chemotherapeutics (melphalan) and corticosteroids (dexamethasone) and new drugs, such as proteasome inhibitors (bortezomib) and immunomodulatory drugs (lenalidomide). Despite improvements in treatment, these regimens do not cure patients, and MM repeatedly relapses until the patient succumbs to the disease. Mechanisms of drug resistance are the expression of drug efflux transporters, inducing gene mutation and expression, adaptation of apoptosis machinery and tumor microenvironment-induced resistance. We are investigating resistance mechanisms in MM cells induced by clinically used agents and by the BM microenvironment.

Increasing evidence demonstrates that epigenetic changes play a major role in MM pathogenesis. The best known epigenetic changes are (i) DNA methylation, (ii) post-translational (non) histone changes (e.g. acetylation, methylation, phosphorylation,….) and (iii) miRNA. DNA methylation is catalyzed by the DNA methyltransferases (DNMT), while the degree of histone acetylation is determined by the activity of the histone acetyltransferases and histone deacetylases (HDACs). These 3 major epigenetic changes have been extensively shown to co-operate intensively in regulating gene expression. Consequently, only minor changes in this major network can have a profound impact on the gene expression. In cancer cells, the promoter-associated CpG islands of tumor suppressor genes or genes encoding for miRNAs are often hypermethylated and acetylated resulting in loss-of-function. In MM, so far, hypermethylation of approximately 30 cancer related genes has been reported. Interestingly, despite the fact that these changes are heritable they are reversible and are thus new potential targets for MM therapy. Indeed, numerous in vitro and preclinical studies have already proven potent anti-MM activity of epigenetic modulating agents. However, the mechanisms by which these agents mediate their anti-tumor effects, especially in vivo where the cells are protected by the bone microenvironment, are still poorly understood and remain to be elucidated. Moreover, so far, no in vitro studies nor preclinical in vivo studies exploring the possible enhanced anti-MM effect of combining a HDAC inhibitor (HDACi) and a DNMT inhibitor (DNMTi) have been conducted. In the lab we are investigating the therapeutic effects and the underlying mechanisms of the HDACi JNJ-26481585 and/ or the DNMTi decitabine in vitro and in vivo by using the 5T33MM mouse model. This should not only enhance our comprehension of what biological mechanisms drive MM progression, but could also contribute to the identification of new molecular targets and provide us with new rationales for combination strategies and perhaps lead to the identification of molecular markers for early detection of cancer, prediction of prognosis and prediction of treatment outcomes.

Mesenchymal stem cells (MSCs) are BM derived multipotent non-haematopoietic progenitor cells that can differentiate into various mesodermal cell types (such as chondrocytes, osteoblasts, adipocytes and myocytes). They also give rise to BM stromal cells and can therefore be considered as the “stromal stem cells”. MSCs and more differentiated stromal cells can produce a wide variety of cytokines and growth factors Since MSCs can be easily expanded in vitro (even at a clinical scale) they are currently used in various preclinical studies and clinical trials for regeneration of injured or diseased mesodermal tissues and for supporting hematopoiesis after HSC transplantation. MSCs have also been shown to have homing ability to tumor-infiltrated tissues and are therefore also tested as vehicle cells for gene therapy in different tumor models Although MSCs have been considered to have potential for cell therapy applications in cancer, several studies have shown that MSCs might also play an active role in the pathogenesis and progression of tumors. Indeed, recent evidence showed that as the precursor of most stromal cells, MSCs can actively migrate to and proliferate in tumors contributing to the tumor-associated stroma. In this project we aim to investigate how MM-BM derived MSCs contribute to the regulation of tumor growth and the induction of bone disease. We examine whether MM-BM MSCs express aberrant features and whether these abnormalities are MM-cell induced or intrinsic. We also test whether endogenous MSCs in MM can be therapeutically targeted and evaluate the effect of new MM drugs on MMBM MSCs. At last we examine whether normal (donor-derived) MSCs can be used as an efficient and safe tool to deliver anti-MM transgene products in the tumor microenvironment.

 

 

 



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  ©2004-2014 • HEIM • Vrije Universiteit Brussel • Faculteit Geneeskunde & Farmacie • Laarbeeklaan 103 • 1090 Jette • Tel.: (+32)-(0)2-477.44.06 • heim@vub.ac.be

17/04/05