Current Research Recipients

CRISPR-BASED FUNCTIONAL CHARACTERIZATION OF WM CELLS: INSIGHTS INTO THERAPEUTIC VULNERABILITIES AND STRATEGIES TO OVERCOME RESISTANCE

Project Period 10/ 01/19 – 10/01/21 Investigator: Constantine Mitsiades, MD, PHD
$400,000 over two years Institution: Dana-Farber, Boston, USA

This project falls under the IWMF-LLS Strategic Research Roadmap Initiative. The research takes advantage of new technologies, including the gene editing tool CRISPR, improved and powerful computational approaches, and innovative new mouse models. The researchers will conduct a broad, genome-wide search to identify specific genes that are required to allow Waldenström’s macroglobulinemia (WM) cells to thrive. Additionally, the researchers will attempt to identify genes that allow WM cells to resist established therapies. The key is to identify specific gene targets that cause death of WM cells, but do not alter normal body cells. Any genes identified will be further tested in laboratory cells and then evaluated in mouse models. This research will hopefully identify new, previously unsuspected molecular targets for WM therapy.

TOWARDS A RATIONAL TARGETED THERAPY FOR WALDENSTRÖM MACROGLOBULINEMIA BY KINOME-CENTERED LOSS-OF-ADHESION AND SYNTHETIC LETHALITY SCREENS

Project Period 03/01/20 – 03/01/22 Investigator: Marcel Spaargaren, PhD; Steven T. Pals, MD, PhD; and Marie Jose Kersten, MD, PhD
$398,000 over two years Institution: Academic MC, Amsterdam, The Netherlands

This project falls under the IWMF-LLS Strategic Research Roadmap Initiative. One mechanism of action of ibrutinib is to dislodge WM cells from the bone marrow, where they grow best. This research seeks to identify specific kinases that allow WM cells to remain in the bone marrow. In a second part of the project, the researchers will seek to identify kinases that allow some of the ibrutinib-surviving cells to survive. In previous IWMF-funded research, Dr Spaargaren’s group identified a set of kinases with potential as new WM drug targets. In the present grant period, they will continue this work, first by validating the new targets in cellular tests (“in vitro”) and then by evaluating the role of the new targets in an innovative mouse model (“In vivo”). Identifying these new protein targets can help determine if there are existing drugs that may be re-purposed to treat WM, or could lead to development of new drugs specific to WM.

DIRECT TARGETING THE MYD88 L265P DRIVER MUTATION IN WALDENSTROM’S MACROGLOBULINEMIA

Project Period 10/15/2019-10/15/2021 Investigator: Yong Li, PhD
$400,000 over two years Institution: Baylor Medical School, Houston, 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.

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 project is sponsored in part by the David and Janet Bingham Research Fund of the IWMF. 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 9/1/2020 – 9/1/2022 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 project is sponsored in part by the David and Janet Bingham Research Fund of the IWMF and the Yang Family Research Fund of the IWMF. 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.

 

EPIGENETIC REGULATION OF WM BIOLOGY

Project Period 9/15/2018 – 3/15/2021 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.

 

ANTI-TUMOR AND IMMUNE MICROENVIRONMENT RESPONSES FOLLOWING A FIRST-IN-HUMAN DNA FUSION VACCINE FOR ASYMPTOMATIC WM/LPL

Project Period 10/15/2017 – 10/15/2021 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 is sponsored in part by the Elting Family Research Fund of the IWMF and the Ed and Toni Saboe Research Fund of the IWMF. 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.

 

MULTIOMIC ANALYSIS OF DNA, RNA AND EPIGENOMIC NETWORKS FOR PROGNOSTICATION AND NOVEL TARGET IDENTIFICATION IN WALDENSTROM’S MACROGLOBULINEMIA

Project Period 09/01/20 – 09/01/22 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.

MYD88L265P SIGNALING-ASSOCIATED MULTIPLEX CHARACTERIZATION OF THE BONE MARROW MICROENVIRONMENT IN WM PATIENTS FOR CLINICAL APPLICATION

Project Period 11/01/20 – 11/01/22 Investigator: Rueben Carrasco, MD, 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.