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).
IDENTIFICATION OF GERMLINE AND SOMATIC VARIANTS ASSOCIATED WITH PREDISPOSITION OF WALDENSTROM MACROGLOBULINEMIA
|Project Period: 11/1/2014 – 10/31/2016||Investigators: Steven P.Treon, MD, PhD, & Zachary Hunter, PhD|
|$361,152.00 over two years||Institution: Dana-Farber Cancer Institute|
Human cancers, including Waldenstrom’s macroglobulinemia (WM), are caused in part by DNA mutations. DNA sequencing technology has identifIed the “L265P” mutation in the gene MYD88 which is present in more than 90% of WM patients and WHIM-like mutations in CXCR4 which are found in about 35% of WM patients. Both of these mutations cause these genes to become activated, which helps the WM cells survive and grow. Mutations in MYD88 alone do not appear to be sufficient to cause cancer. This project will sequence the regions of DNA which have been identified as being associated with WM predisposition in 1000 WM patients and their family members: predisposing DNA code that may exist in these regions will be assessed regarding how prevalent these inherited variants (mutations) are in the Familial WM cases, as well as the WM population in general. Aim 2 will use the information gained from the results arising from Aim 1 and perform cellular studies to understand their contribution to signaling that supports WM growth and survival. This information will then enable the rationale design of targeted drugs against these functions. Aim 3 will study if any of these predispositions lead to differences in overall survival, response the therapy, or are associated with clinical characteristics such as high IgM or lymph node involvement.
MUTANT MYD88: A TARGET FOR ADOPTIVE T CELL THERAPY OF WM
|Project Period: 10/15/2014 – 10/15/2016||Investigators: Brad H Nelson, PhD, Julie S Nielsen, PhD|
|$ 370,748.00 (CDN) over two years||Institution: BC Cancer Agency|
A T cell receptor that recognizes an abnormal form of a protein called MYD88, found in the vast majority of WM tumors, was recently identified in WM. This T cell receptor can be used to endow patient’s T cells with the capacity to recognize and destroy their tumor. The researchers are pursuing a new treatment strategy in which T cells from WM patients will be engineered to express this T cell receptor. Patients will then be infused with large numbers of these engineered T cells. The T cells are expected to recognize and destroy tumor cells throughout the body, leading to improved tumor control and possibly cure.
This study is jointly funded by the IWMF and Waldenstrom’s Macroglobulinemia Foundation of Canada.
LARGE SCALE GENOMIC AND PROTEOMIC PROFILING IN WALDENSTROM’S MACROGLOBULINEMIA
|Project Period: 9/1/2010 - 08/31/2016||Investigator: Irene Ghobrial, MD|
|$900,000.00 over 5+ years||Institution: Dana Farber Cancer Institute|
This ia a study to develop a tissue bank of WM specimens linked to clinical characteristics of patients in different stages of the disease, to characterize the genetics and proteomics of WM cells during disease progression, and to develop biomarkers that evaluate in vivo activity of therapeutic agents in WM patients treated in clinical trials. You can participate in the Tissue Bank - click here.