NON-INVASIVE DIAGNOSTICS AND MONITORING OF MRD [MINIMAL RESIDUAL DISEASE] AND CLONAL EVOLUTION OF WALDENSTRÖM’S MACROGLOBULINEMIA
|Project Period 10/15/2017 – 10/15/2019||Investigator: Marzia Varettoni, MD|
|$400,000 over two years||Institution: Fondazione Italiana Linfomi Onlus (FIL), Alessandria, Italy|
This project falls under the IWMF-LLS Strategic Research Roadmap Initiative. Dr. Varettoni hypothesizes that a reliable diagnosis, as well as the differentiation of IgM-MGUS from WM, may be done in the clinical setting without the need for invasive procedures such as bone marrow or lymph node biopsies. She also suggests that the assessment of minimal residual disease (MRD) is feasible in WM, that MRD can predict relapse in WM patients receiving therapy, and that this assessment can be performed on both bone marrow and peripheral blood samples. Dr. Varettoni also proposes that the dynamics of clonal evolution in WM can be monitored in bone marrow and peripheral blood and can potentially guide a tailored treatment choice.
ANTI-TUMOR AND IMMUNE MICROENVIRONMENT RESPONSES FOLLOWING A FIRST-IN-HUMAN DNA FUSION VACCINE FOR ASYMPTOMATIC WM/LPL
|Project Period 10/15/2017 – 10/15/2019||Investigator: Larry W. Kwak, MD, PhD|
|$400,000 over two years||Institution: Beckman Research Institute of the City of Hope, Duarte, CA, USA|
This project falls under the IWMF-LLS Strategic Research Roadmap Initiative. WM/LPL (lymphoplasmacytic lymphoma) is characterized by an asymptomatic phase during which currently available therapies are associated with toxicities and provide no overall survival benefit – hence the current strategy of “watch and wait.” A more efficient, non-toxic alternative therapy is therefore needed in this early disease setting. The surface IgM immunoglobulin of malignant B-cells, formed by the combination of the variable regions of heavy and light chains, can act as a tumor-specific marker of the malignant clone and can thus be used as a target to develop a vaccine therapy. Dr. Kwak’s group now has the ability to clone the genes in the variable region of the immunoglobulin and combine them into a single chain antigen format (scFv) to be used as a DNA vaccine. This vaccine is the subject of a cooperative single-center Phase I safety study being conducted at MD Anderson Cancer Center by Dr. Sheeba Thomas. Analysis of pre- and post-vaccination blood and bone marrow samples to determine the vaccine’s effectiveness will be performed by Dr. Kwak’s group at the City of Hope.
NOVEL ANTIBODY-TARGETED INTERFERONS IN COMBINATORIAL THERAPIES FOR WALDENSTROM’S MACROGLOBULINEMIA
|Project Period 9/15/2017 – 9/15/2019||Investigator: Sherie Morrison, PhD|
|$400,000 over two years||Institution: David Geffen School of Medicine, University of California, Los Angeles, CA, USA|
This project falls under the IWMF-LLS Strategic Research Roadmap Initiative. Interferons are cell proteins with a broad spectrum of anti-cancer activities and have been used for cancer treatment. But to date, the side effects associated with interferon have limited its use as a therapeutic agent. By fusing an interferon with a targeted antibody, Dr. Morrison suggests that the interferon can be made more effective without resulting in systemic toxicity. Dr. Morrison proposes to determine the efficacy of antibody-IFN fusion proteins for the treatment of WM. She will compare 8 different fusion proteins, as single agents and in combinations, in the laboratory and then test these fusion proteins in mice engrafted with WM cell lines. She will also determine if IFN fusion proteins can synergize with the established WM therapies bortezomib and ibrutinib.
FROM BIOLOGY TO TREATMENT: PROGNOSTIC FACTORS, BONE MARROW MICROENVIRONMENT, GENOMIC AND PROTEOMIC PROFILE OF LIGHT CHAIN AMYLOIDOSIS IN WALDENSTRÖM’S MACROGLOBULINEMIA
|Project Period 10/1/2017 – 10/1/2019||Investigator: Morie Gertz, MD|
|$200,000 over two years||Institution: Mayo Clinic, Rochester, MN, USA|
Amyloidosis in WM is a rare condition that occurs when the free light chains produced by the clonal B-cells develop into an abnormally folded protein called amyloid that cannot be broken down. Amyloid can form deposits in different organs, most commonly the kidneys, and cause serious damage. There are currently no individualized treatment approaches for WM patients with amyloidosis. With the ultimate goal to determine the best therapeutic strategies for these patients, Dr. Gertz will perform in-depth studies to describe the clinical characteristics and biology of amyloidosis in WM. This work is intended to discover the factors that trigger the condition in patients with WM and IgM-MGUS, to determine why the deposits of amyloid protein tend to occur in certain tissues, and to identify prognostic factors unique to this condition.
MODULATION OF T-CELL FUNCTION BY METABOLOMIC SIGNATURE OF THE BONE MARROW MICROENVIRONMENT IN WALDENSTROM’S MACROGLOBULINEMIA
|Project Period 9/15/2017 – 9/15/2019||Investigator: Shahrzad Jalali, PhD|
|$400,000 over two years||Institution: Mayo Clinic, Rochester, MN, USA|
This project falls under the IWMF-LLS Strategic Research Roadmap Initiative. There are data to indicate that amino acids are key regulators of immune response and tumor growth in several cancers. For instance, L-arginine is an essential amino acid that regulates T-cell cycle progression, and depletion of L-arginine by myeloid derived suppressor cells (MDSCs) leads to an inhibition of T-cell proliferation. Depletion of the amino acids cysteine and cystine has also been shown to inhibit T-cell function and is mediated by MDSCs. Given that MDSCs are immunosuppressive cells that inhibit T-cell function, Dr. Jalali hypothesizes that the number and activity of these cells are increased in WM and that their accumulation results in depletion of key amino acids. To prove her hypothesis, Dr. Jalali plans to perform a targeted metabolomic analysis on bone marrow, serum, and urine samples in a larger group of WM patients, including smoldering and symptomatic WM, as well as patients who have had a response to therapy. She will assess MDSC cell number and activity in WM patients and study whether increased activity contributes to amino acid depletion in the bone marrow. She will determine whether MDSCs and amino acid depletion suppress T-cell function and promote tumor cell growth.
SINGLE-CELL NEXT-GENERATION FLOW AND SEQUENCING TO UNRAVEL THE PATHOGENESIS OF WALDENSTRÖM’S MACROGLOBULINEMIA AND TO DESIGN GENETICALLY-DRIVEN HUMAN-LIKE EXPERIMENTAL MODELS
|Project Period 9/15/2017 – 9/15/2019||Investigator: Bruno Paiva, PhD, and Jose Angel Martinez-Climent, MD, PhD|
|$400,000 over two years||Institution: Clinica Universidad de Navarra (CUN) and Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain|
This project falls under the IWMF-LLS Strategic Research Roadmap Initiative. The transformation from a normal cell to a cancer cell involves a series of changes driven by a step-wise accumulation of genetic alterations. The mechanisms behind the malignant transformation of WM remain largely unknown. Although the MYD88 L265P mutation may be considered an important event in this transformation, the mutation by itself cannot explain the development of WM from IgM-MGUS. In this research project, Dr. Pavia and Dr. Martinez-Climent will investigate the cellular origin of WM by using next-generation flow cytometry and gene sequencing technologies in samples of patients with IgM-MGUS and WM and use this information to develop genetically-driven experimental WM mouse models.
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 extended to 12/31/2017||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).