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Current Research Recipients

FACTORS REGULATING IMMUNOGLOBULIN-PRODUCING B-CELLS IN PATIENTS WITH WALDENSTROM’S MACROGLOBULINEMIA – PART V

Project Period 1/1/2019-12/31/2020

Investigator: Stephen Ansell, MD, PhD

$428,146 over two years

Institution: Mayo Clinic, Rochester, MN, USA 

This is a continuation of previous projects proposed by Dr. Ansell and funded by the IWMF. While recent studies have provided considerable insight into the genetic events occurring in the WM cell, less is known about the influence of the bone marrow microenvironment on WM development. Myeloid derived suppressor cells (MDSCs) are a group of immature immune cells that can give rise to macrophages, granulocytes, and dendritic cells. They can also strongly expand in disease situations such as chronic infections and cancer and have the ability to suppress T-cell function. Dr. Ansell proposes that these MDSCs are important in the bone marrow microenvironment of WM patients and may be involved in suppression of normal immune cells so that they are not doing their job of killing the cancer cells. To test his hypothesis, Dr. Ansell and his team will define the characteristics and function of MDSCs in the WM bone marrow, determine whether WM cells promote the development of MDSCs, assess whether MDSCs not only suppress immune function but also directly promote WM cell growth, and determine whether MDSCs can be altered so that they can instead become immune cells effective in killing WM cells. This work may lead to a new therapeutic approach for WM patients.  

TARGETING MYD88 SIGNALING IN WALDENSTROM’S MACROGLOBULINEMIA

Project Period 9/1/2018 - 8/31/2020       

Investigator: Principal Investigator Steven Treon, MD, PhD, and Co-Investigator Guang Yang, PhD

$500,000 over two years

Institution: Dana-Farber Cancer Institute, Boston, MA, USA 

This is a continuation of previous projects proposed by Dr. Treon and funded by the IWMF. In previous research partially funded by the IWMF, Dr. Treon and his team discovered the highly recurring mutation in the MYD88 gene that occurs in more than 90% of WM patients and showed that mutated MYD88 promoted growth and proliferation of WM cells through the downstream signaling pathways BTK and IRAK1/IRAK4. These findings enabled the pivotal clinical trial that led to approval of the BTK inhibitor ibrutinib (Imbruvica) for the treatment of WM in the US, Europe, and Canada. Resistance to ibrutinib is an emerging problem in WM patients, and Dr. Treon’s team has identified mutations in BTK that disrupt ibrutinib-BTK binding in samples from half of WM patients whose disease progressed on ibrutinib. His group has sought novel strategies to overcome the most common type of BTK mutation-related ibrutinib resistance in WM. His group is also working on uncovering the importance of other MYD88 downstream signaling pathways, included HCK, AKT, and ERK1/2. For this project, Dr. Treon has three principal Aims: 1) to delineate the importance of IRAK signaling to ibrutinib resistance and develop selective IRAK inhibitors based on this work, 2) to clarify whether HCK inhibition can suppress mutated BTK-acquired ibrutinib resistance in WM and develop selective HCK inhibitors, and 3) to validate these inhibitors alone and in combination using animal models for future translation to clinical trials.

TRANSCRIPTIONAL CHARACTERIZATION OF UNTREATED PATIENTS WITH WALDENSTROM’S MACROGLOBULINEMIA

Project Period 9/1/2018 - 8/31/2020

Investigator: Principal Investigator Steven Treon, MD, PhD, and Co-Investigator Zachary Hunter, PhD

$400,000 over two years

Institution: Dana-Farber Cancer Institute, Boston, MA, USA 

This project falls under the IWMF-LLS Strategic Research Roadmap Initiative. The genome is made up of DNA, a long, winding molecule that contains the instructions needed to build, maintain, and reproduce cells. For these instructions to be carried out, DNA must be “read” and transcribed—in other words, copied—into RNA molecules, which are called “transcripts.” A “transcriptome” is a collection of all the RNA transcripts present in a cell. A comprehensive characterization of the RNA transcriptome provides a snapshot of the inner workings of a cell at a particular moment in time. Studying the RNA transcriptome is a way in which researchers can determine when, where, and how each gene is expressed in a cell. This in turn can provide a basis for comparison between how genes are expressed in normal cells versus how they are expressed in cancer cells. Dr. Treon and Dr. Hunter propose to sequence the RNA transcriptome of a much larger set of WM patient samples than previously studied. Their sample set from 300 untreated patients should provide robust numbers for statistical analysis, thereby leading to better evaluation of gene expression from different types of MYD88 and CXCR4 mutations and better characterization of gene expression of other, less understood mutations in genes such as CD79B, ARID1A, and TP53, among others. Patients who provide samples will continue to be followed over time to investigate whether and how their gene expression patterns correlate with the clinical characteristics of their disease, such as: disease progression, response to therapy, subsequent progression-free survival and overall survival, and other events relevant to the natural course of WM.

EPIGENETIC REGULATION OF WM BIOLOGY

Project Period 9/15/2018 – 9/15/2020

Investigator: Sherine Elsawa, PhD

$400,000 over two years

Institution: University of New Hampshire, Durham, NH, USA 

This project falls under the IWMF-LLS Strategic Research Roadmap Initiative. Although several genetic alterations in the development of WM have been identified, very few advances have been made in understanding the epigenetic landscape controlling the biology of the disease. The word epigenetics literally means “above genetics.” It is the study of variations caused by external factors that switch genes on and off and affect how genes are “read.” Like DNA, these epigenetic variations can be passed on from cell to cell. We currently know of several methods by which these epigenetic variations affect genes. One is by histone modification. Histones are spool-like proteins that enable the DNA molecule to be tightly coiled into chromosomes. A variety of chemicals can affect histones, changing how tightly or loosely they package DNA. If the wrapping is tight, a gene may be “hidden” in the DNA strand and consequently switched off; if the wrapping is looser, a gene that was formerly hidden may now be turned on. Many enzymes involved in histone modification have been reported to be abnormally expressed in different malignancies, although most of these are just beginning to be explored in WM. An enzyme called MLL1 is best known for its role in leukemia; however, previously no role for MLL1 in WM has been described. Dr. Elsawa has generated preliminary data indicating that MLL1 is highly expressed in WM cell lines and in WM cells from patient samples, and she suggests that defining the impact of MLL1 in WM could be a possible breakthrough in understanding the epigenetic regulation of the disease. Dr. Elsawa’s central hypothesis is that MLL1 activates key genes, particularly IL-6 and CCL2, which play an important role in WM biology through the Toll-like receptor/MYD88 pathway. She will perform several experiments with cell lines, patient samples, and animal models to confirm her hypothesis.

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 José 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, extended to 5/15/2019

Investigator: Madhav Dhodapkar, MB, BS

$400,000 over two years

Institution: Emory University, Atlanta, GA, USA 

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.

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