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The influence of cellular interactions within the bone marrow on drug resistance in Multiple Myeloma

Principal Investigator: Eline Menu

Participants: Sylvia Faict; Inge Oudaert

Multiple Myeloma cells develop drug resistance, partially through interactions with the bone marrow (BM) microenvironment. In the team of Eline, we focus on the cross-talk between the tumor cells and the surrounding BM cells. Two interwoven topics are studied: metabolic changes induced by the BM environment in the tumor cells AND the involvement of extracellular vesicles, termed exosomes, in the cross-talk between BM stromal cells and MM cells. The team has access to a Zeta View particle analyzer to quantify exosomes and has published multiple papers demonstrating the involvement of exosomes not only in MM drug resistance but also in modulation of the BM environment. Since the BM is a naturally hypoxic region, MM cells need to adapt their metabolism to their surroundings. Moreover, the BM can induce a metabolic symbiosis by providing necessary metabolites to the tumor cells. The Menu team is now examining whether exosomes also play a role in this process.

Targeting of tumor subpopulations: protein/gene expression analysis of residual cancer cells and targeting of these cells using

Principal Investigator: Kim De Veirman

Despite significant therapeutic advances, multiple myeloma remains incurable for the majority of patients as they inevitably relapse due to an incomplete eradication of residual cancer cells. In collaboration with the lab of Prof. Peter Croucher (Garvan Institute of Medical Research, Sydney, Australia) we recently demonstrated for the first time the presence of dormant myeloma cells by longitudinal intravital two-photon imaging. These quiescent cells were resistant to chemotherapy and demonstrated differences in gene expression compared to dividing cancer cells. Importantly, myeloma cell dormancy was a reversible state controlled by the endosteal niche containing osteoblasts and osteoclasts. Furthermore, gene array analysis identified some specific genes (e.g. Axl, CS1 and VCAM1) that were significantly upregulated in quiescent cells compared to proliferating cells. Importantly, these upregulated genes can serve as potential therapeutic targets to eradicate the remaining cancer cells after initial treatments and prevent relapse of myeloma patients.

The objective of this project is to specifically target residual cancer cells by the use of nanobodies. Compared to conventional antibodies, camelid-derived nanobodies are extremely small, very stable and easy to manufacture. Nanobodies are directed against tumor-specific antigens CS1 and Axl. Anti-CS1 nanobodies will be charged with beta- and alfa-emitting radionuclides killing both bulky and neighboring dormant cells. Antagonistic Axl-targeting nanobodies will be developed to reverse myeloma cell dormancy and subsequently increase chemosensitivity. This may provide a complementary approach to current treatments (e.g. chemotherapy, proteasome inhibitors), which target only the rapidly dividing myeloma cells.

Specific targeting of epiplayers driving drug resistance in multiple myeloma: paving the way to personalized treatment?

Principal Investigator: Elke De Bruyne

Participant: Eva De Smedt

The need for biomarker-driven personalized cancer treatment to further improve patient outcome is becoming increasingly apparent. While cancer is typically considered a genetic disease, epigenetic lesions are now also widely recognized to contribute to most of the classical hallmarks of cancer, including but not limited to genomic instability, sustained proliferation, invasion and metastasis, drug resistance, evasion of the immune system and metabolic dysregulation. Moreover, an increasing number of non-recurrent mutations in epigenetic modifiers (epiplayers) have been identified in cancer cells and these seem to increase in frequency upon relapse. Like in cancer in general, numerous epigenetic defects have also been identified  in MM (including locus-specific DNA hypermethylation of cancer-related and B cell specific genes, genome-wide DNA hypomethylation and somatic mutations, copy number variations and/or abnormal expression patterns of a large variety of epigenetic modifying enzymes) and have been linked with genomic instability, drug resistance, disease progression and high risk disease. However, for many epiplayers their exact role in MM cell biology and drug resistance remains poorly defined. The past 10 years, team ‘epigenetics’ has investigated the epigenetic regulation of malignant plasma cells within the supportive bone marrow and the therapeutic and diagnostic potential of pan-HDACi and DNMTi in MM. As a logical continuation of our past research, we now wish to expand our knowledge of the role of epiplayers in drug resistance in MM and cancer in general. Specifically, we aim to identify (new) epiplayers mediating drug resistance and evaluate whether they can be useful as i) predictive marker for drug response and ii) therapeutic target for personalized treatment.

Exploring the therapeutic potential of targeting mitotic exit for high grade B cell malignancies

Principal Investigator: Elke De Bruyne

Participants: Anke Maes

Non-Hodgkin lymphoma (NHL) is the most common hematological malignancy, accounting for about 4% of all cancers. NHL can occur at any age, consists of many different subtypes and is further subdivided into low grade (indolent) and high grade (aggressive) NHLs. Diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) are two high grade B-cell NHLs, accounting for respectively 30% and 2-10% of all NHL cases. Standard therapy for these aggressive NHLs is R-CHOP, consisting of rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone. Despite the significant improvement of the survival rates with the introduction of the R-CHOP regimen in the treatment of DLBCL and MCL, virtually all MCL patients and ±30% of the DLBCL patients still relapse and die of non-responsive disease. Moreover, patients with high risk disease continue to face early relapse and death. A common feature shared by all high risk and relapsed MCL and DLBCL cases is the presence of a high proliferation index. While studies in MCL and DLBCL have so far mainly focused on targeting the cell cycle at the level of either interphase, spindle assembly or mitotic entry, increasing evidence indicates that targeting mitotic exit in cancer cells might be a better strategy since inhibition of mitotic exit causes a more permanent mitotic arrest subsequently leading to mitotic cell death. The general goal of this project is to explore the therapeutic potential of targeting proteins involved in mitotic exit, alone and in combination with standard of care (SOC) agents, in DLBCL and MCL. This project is further subdivided in 2 specific aims:

  1. To investigate the therapeutic potential of blocking the anaphase promoting complex/cyclosome (APC/C) and its co-activator Cdc20 in DLBCL and MCL.
  2. To investigate the therapeutic potential of maternal embryonic leucine zipper kinase (MELK) targeting in DLBCL and MCL.

High Risk Myeloma and Immune modulation

Principal Investigator: Ken Maes

Participants: Philip Vlummens

The first research line focuses on the identification of high-risk phenotypes in cancer, in particular in haematological cancers including multiple myeloma. This information can be extracted from the integration of transcriptomics, genomics and clinical data and be used to identify novel targets for the treatment of patients with high risk phenotpyes. One example that we are studying is based on the connection of DNA repair and epigenetic pathways that contribute to high-risk features in multiple myeloma. Within this gene signature, we identified protein arginine methyltransferase 5 as a novel target for high-risk myeloma patients. The second research line is related to onco-immunology. In this project, we aim to characterize the presence and function of different immune cells in the bone marrow of multiple myeloma patients using flow cytometry, single cell RNA sequencing and co-culture assays. Myeloma is characterized by a compromised immunity against the malignant plasma cells. By understanding the bone marrow cellular composition and potential functional interactions between immune cells and myeloma cells, we aim to enhance the anti-myeloma immune response.

Liquid biopsies and circulating biomarkers for disease characterization and monitoring in multiple myeloma

Principal Investigator: Ivan Van Riet

Participants: Marleen Bakkus, Rik Schots, Wouter De Brouwer, Robbe Heestermans

During the last decade, an impressive progression has been made in the treatment possibilities and clinical outcome of multiple myeloma. However, the availability of new drugs and additional therapeutical options cannot prevent that most patients relapse and become refractory to treatment at a certain stage in their disease evolution. Multiple myeloma is characterized by a patchy tumor distribution pattern in the bone marrow, implicating that single bone marrow sampling during diagnostic working up, can lead to underestimation of the true tumor heterogeneity. Moreover, a better disease follow-up during and after treatment requires a more frequent analysis of minimal residual disease as well as genetic profiling at the moment of relapse or refractory disease. Therefore, there is much interest in the development of peripheral blood-based monitoring methods that could allow more frequent sampling without the discomfort of repeated bone marrow aspirations. This project aims to identify and characterize different circulating markers for diagnosis and disease monitoring in multiple myeloma. In particular we focus on circulating tumor cells, cell-free DNA and exosomes-derived DNA for their potential and clinical value in mutation profiling and disease monitoring. It is important that such markers are fully validated in relation to the biology and clinical features of this disease, before they can be finally used in clinical practice.

Cell processing for hematopoetic (stem) cell therapies

Principal Investigator: Ivan Van Riet

Participants: Rik Schots, Ann De Becker

Autologous and allogeneic stem cell transplantations (from bone marrow, peripheral blood and cord blood) became through the last three decades a standard therapy for various hematological, (mostly) malignant disorders. Over the years, there has been besides the evolution in the pre-transplantation conditioning regimens and the control of clinical complications also further progress in the graft collection and processing technology. In parallel there is increasing interest to use peripheral blood–derived cells for immune effector cell therapy in different types of hematological and solid cancers. The department Hematology UZ Brussel has a JACIE-accredited stem cell transplantation program and a FAGG-licensed bank for hematopoetic stem cells, donor lymphocytes and dendritic cells. All technologies are available for research and clinical scale cell isolation, cell cryopreservation and graft quality testing. Research (and research collaboration) is focused on characterization of in vitro expanded mesenchymal stem cells and cell processing  for new immune effector cell therapies.

Study of clinical presentation and molecular mechanisms responsible for inherited antithrombin deficiency

Principal investigator: Prof. Dr. Kristin Jochmans

Participants: Christelle Orlando, MSc

Inherited antithrombin (AT) deficiency is a very rare thrombophilic condition that is associated with thrombosis at young age, familial history of VTE, recurrent events and the presence concomitant risk factors. Over the past 20 years, our center has become a reference center for inherited antithrombin deficiency. Besides phenotypical characterization, we are the only Belgian center performing molecular analysis to unravel the genetic background of inherited AT deficiency. This has revealed that thrombotic complications are linked to the genotype of the patients, emphasizing the added value of performing the genetic studies to provide better patient care. More surprisingly, some mutations seem to be associated with arterial thrombosis. The exact mechanism is currently unknown and will be further the explored. By studying unreported mutations in recombinant in vitro experiments, novel pathogenic mechanisms can be identified, leading to a better understanding of the disease.

High sensitive detection of monoclonal B-cell lymphocytosis

Principal investigator: Prof. Dr. Kristin Jochmans

Participants: Dr. Sam Vander Meeren

The research topic is that of the small B-cell clones in the peripheral blood, the so called monoclonal B-cell lymphocytosis (MBL), a relatively benign entity that is detected with flow cytometry. It is a new research domain with still lots of opportunities for exploration. Most MBL studies up until now describe MBL with a chronic lymphocytic leukemia immunophenotype (C-MBL) because they are the most common and easiest form of MBL to detect. MBL with a lymphoma-like immunophenotype (L-MBL) is largely unexplored, presumably because it is harder to detect. Its clinical course especially, i.e. evolution towards B-cell non-Hodgkin lymphoma, remains unknown. The goals of this project are threefold. First off, it is the intention to better characterize L-MBL by studying its biology and clinical outcome in a hospital population. Secondly, we wish to study the immunological aspects in MBL (C-MBL and L-MBL) subjects, such as the T-cell response and the serum immunoglobulin secretion. Lastly, we want to ameliorate the detection rate of B-cell lymphoproliferative diseases (and thus of L-MBL) by implementing a new flow cytometer into the laboratory together with improved and expanded antibody combinations and novel gating strategies. By doing so, it will be possible to have a more accurate estimate of the frequency of MBL in healthy subjects and patients with a B-lymphoid related ailment such as myeloma and possibly idiopathic thrombocytopenic purpura, while also acquiring more information regarding the antigen expression of these clones.

Determining Minimal Residual Disease (MRD) in patients with Acute Lymphatic Leukemia

Principal Investigator: Marleen Bakkus

The detection of residual disease after initial chemotherapy determines the prognosis for children with ALL. If MRD can be detected, these children will receive a more intense treatment strategy, thereby improving their survival rates. It is therefore important to have the most sensitive method possible to determine MRD. In this project, a specific PCR technique has been developed and optimized to detect MRD. Currently, this PCR technique is now recognized as the golden standard. However, this techniqe is labor-intensive and can only be used in a number of reference laboratories. To improve this technique, we are now investigating the use of NGS to improve sensitivity, specificity and efficiency.

The Role of HLA and KIR Polymorphisms in the Clinical Outcome Of COVID-19 Infected Patients

Principle Investigator: Barbara Depreter

Participants: Ann De Becker, Kristin Jochmans

Although the majority of patients with COVID-19 are thought to have mild symptoms, some of them will have severe illness that progress to acute respiratory distress syndrome (ARDS). This lung inflammation would be mediated by immunological reactions. It is well known that genetic differences contribute to different immune response to pathogens. The Human Leucocyte Antigen (I-ILA) molecules, encoded by the most polymorphic genes in the human population, are cell surface glycoproteins responsible for the presentation of foreign peptides for immune surveillance. Such life-threatening hypersensitivity reaction was observed by HIV patients treated by Abacavir who were positive for HLA-B*57:01 allele. Furthermore, Killerlg-like (KIR) receptors regulate the NK cells in a HLA-dependent manner that are important in the immune defense against viral infection.