TOWARDS A RATIONAL TARGETED THERAPY FOR WALDENSTROM’S MACROGLOBULINEMIA BY KINOME-CENTERED LOSS-OF-ADHESION AND SYNTHETIC LETHALITY SCREENS
|Project Period 1/1/2017 – 1/1/2019||Investigator: Marcel Spaargaren, PhD; Steven T. Pals, MD, PhD; and Marie Jose Kersten, MD, PhD|
|$389,000 over two years||Institution: Academic Medical Center, Amsterdam, The Netherlands|
This project falls under the IWMF-LLS Strategic Research Roadmap Initiative. Some patients have primary resistance to ibrutinib, while a significant subset of patients who receive prolonged treatment with it develop secondary resistance due to recurrent mutations in BTK or its substrate, resulting in a poor clinical outcome. Thus, there is a need for the identification of novel targets and development of novel therapies to prevent or overcome ibrutinib resistance. Dr. Spaargaren and his associates demonstrated that ibrutinib and idelalisib target the B-cell receptor, but not CXCL12/CXCR4-controlled integrin-mediated adhesion in WM. They hypothesize that producing “homelessness” in malignant B-cells by targeting integrin-mediated homing and retention may be a powerful general strategy to cure B-cell malignancies. This project aims to identify the signaling pathways that control integrin-mediated WM cell homing, retention, and outgrowth; to identify kinases whose inhibition makes WM cells sensitive to the effects of ibrutinib and idelalisib; and to explore and exploit their potential as therapeutic targets for novel targeted combination therapy for WM patients.
CHARACTERIZATION OF ENDOGENOUS CXCR4 INHIBITORY PEPTIDES TO TARGET WALDENSTROM’S MACROGLOBULINEMIA
|Project Period 10/31/2016 – 10/31/2018||Investigator: Christian Buske, MD; Jan Münch, PhD; and Daniel Sauter, PhD|
|$389,000 over two years||Institution: Ulm University, Ulm, Germany|
This project falls under the IWMF-LLS Strategic Research Roadmap Initiative. The focus of this grant is on the biological role of CXCR4 mutations, using mouse modeling, and their possible regulation by naturally occurring CXCR4 inhibitors. Almost all CXCR4 mutations in WM cause prolonged signaling upon binding to CXCL12 and may act as cancer-causing partners for the MYD88 L265P mutation in WM. For this project, a novel mouse model that expresses the MYD88 L265P mutation will be used, and the most frequent WM CXCR4 mutations will be introduced. Mice will be analyzed for disease development. The investigators will also determine the effects of CXCR4 inhibitors, as well as the drugs ibrutinib and AMD3100, on WM cell lines that have been encoded with either wild type or mutated CXCR4.
ORIGINS AND IMMUNOTHERAPY OF MACROGLOBULINEMIA
|Project Period 9/15/2016 – 9/15/2018||Investigator: Madhav Dhodapkar, MB, BS|
|$400,000 over two years||Institution: Yale University|
This project falls under the IWMF-LLS Strategic Research Roadmap Initiative. It proposes that a major proportion of WM and IgM MGUS cases involve the transformation of natural IgM memory B-cells and that chronic antigen stimulation of these cells by lipid antigens underlies the pathogenesis of WM. The ability to model/grow precursor states in mice in vivo combined with new insights into the antigenic origins of WM sets the stage to gain fundamental insights and provide a platform to test new biologic or immune-based approaches to test prevention and therapy of WM.
TARGETING MYD88 ASSEMBLY AND DOWNSTREAM SIGNALING IN WALDENSTROM’S MACROGLOBULINEMIA
|Project Period 8/15/2016 – 8/15/2018||Investigator: Steven P. Treon, MD, PhD|
|$498,425 over two years||Institution: Dana-Farber Cancer Institute|
Mutations in MYD88 facilitate self-assembly of the Myddosome (a special complex of proteins) and can trigger NF-kappa B signaling that promotes the growth of WM cells. This project will characterize aspects of Myddosome assembly that promote survival in MY88-mutated WM cells, as well the effects of MYD88 mutations on kinases other than BTK, and will develop and characterize inhibitors to these activating substances.
HYPOXIA-TARGETED PET-IMAGING FOR PREDICTION OF PROGRESSION FROM MGUS TO WALDENSTROM’S MACROGLOBULINEMIA
|Project Period 2/1/2016 – 1/31/2018||Investigator: Abdel Kareem Azab, PhD|
|$187,141 over two years||Institution: Washington University in St. Louis|
The goal of this study is to investigate and develop a molecularly targeted system which can predict progression from MGUS to WM and which will be able to indicate patients with high(er) risk of development of symptomatic WM. Dr. Azab hypothesizes that hypoxia is the “switch” that induces MGUS to become the disseminated form of active WM. He will develop and use a special PET imaging to detect hypoxic metabolism in WM cells, with the amount of binding an indication of their metastatic potential.
THE FACTORS REGULATING IMMUNOGLOBULIN-PRODUCING B-CELLS IN PATIENTS WITH WALDENSTROM’S MACROGLOBULINEMIA
|Project Period 9/1/2015 – 9/1/2018||Investigator: Stephen M. Ansell, MD, PhD|
|$626,136 over three years||Institution: Mayo Clinic, Rochester|
This is a continuation of previous projects proposed by Dr. Ansell and funded by the IWMF. The current study proposes to continue research into the role of the bone marrow microenvironment in regulating IgM production and promoting malignant B-cell growth. The new 3-year proposal builds on previous work by studying the role of PD-1, a receptor that is upregulated by IL-21 and IL-6 via STAT5.
THE UCLH WM BIOBANK: FROM BIOLOGY TO TREATMENT
|Project Period 5/1/2015 – 5/1/2017||Investigators: Shirley D’Sa, MD, et al|
|₤40,000.00 over two years||Institution: University College London Hospitals|
The Serum and Tissue Bank within University College London Hospitals NHS Foundation Trust, London, UK, has a large and growing patient-base of IgM MGUS and WM patients at their centre, amounting to 150 WM/LPL patients and another 100 IgM patients including those with IgM MGUS, paraproteinaemic neuropathies, Bing-Neel syndrome, cold haemagglutinin disease and AL amyloidosis. There is a dedicated WM clinic in which 18-20 patients are seen each week, including 2 new patients on average. The centre receives referrals from across the UK, and is closely allied to WMUK, a unique doctor-patient partnership that has been set up to act as the UK point of contact for patients with WM. The investigators intend to systematically examine the clinical and biological characteristics of persons with these conditions by setting up a Serum and Tissue Bank with the intention of establishing an effective scientific and clinical trials programme for this patient group. A bank of biological samples will greatly enhance the ability to set up clinical trials in this patient group and contribute to the international effort to further significant benefits for patients.
This study is jointly funded by the IWMF and Waldenstrom’s Macroglobulinemia United Kingdom (WMUK).