The International Waldenstrom’s Macroglobulinemia Foundation (IWMF) and The Leukemia & Lymphoma Society (LLS) are proud to announce the third IWMF-LLS STRATEGIC RESEARCH ROADMAP INITIATIVE: A Request for Proposals (RFP) to help further knowledge in four key domains of Waldenstrom’s macroglobulinemia (WM) research:
- Genomics and Epigenomics:
Mutations in signaling pathways that drive cancer provide an opportunity to develop targeted therapies to treat the disease. This is highly relevant to WM, since approximately 90% and 30% of WM patients have mutations in MYD88 and CXCR4, respectively. Moreover, since MYD88 activates interleukin-1 receptor-associated kinase and Bruton’s tyrosine kinase (BTK), this helps to explain why WM patients have a major response to the BTK-targeted agent known as ibrutinib (approved for WM by the Food and Drug Administration, the European Medicines Agency, and Health Canada). Nevertheless, cures have not been achieved with ibrutinib. Furthermore, patients with wild-type MYD88 and/or WHIM-mutated CXCR4 probably have lower response rates and slower response kinetics to ibrutinib. Patients with wild-type MYD88 disease also show differences in clinical presentation, including lower serum IgM and bone marrow disease burden, CD27+ expressing disease, and lymphocytosis, versus mutated MYD88 patients. The genetic basis for wild-type MYD88 disease remains unknown. These data indicate that further genetic analyses, coupled with functional studies tounderstand the effects of mutations in WM, need to be explored further to 1) understand the basis of resistance to existing agents, 2) provide a mechanistic understanding that may
justify combination of therapies, and 3) lead to the development of new therapeutics to specifically control or cure the disease. Recently it has become clear that epigenetic regulators are also important in lymphomas and myelomas. However, relatively little is known about the epigenome in WM. Mutations or copy number losses affecting major chromatin remodeling proteins exist for WM, though their impact on specific gene dysregulation remains unclear. A comprehensive dissection of the epigenome of WM cells genotyped by MYD88 and CXCR4 mutation status will provide critical insights into cellular signaling and pathways for potential therapeutic exploitation. It would be beneficial to develop reliable and sensitive methods to determine if and when patients might be able to terminate therapy if no disease is detected or to identify disease relapse early at the molecular level. For instance, a super-sensitive PCR-based technology to detect MYD88 mutations by utilizing peripheral blood samples would be useful and complement current methodologies that track disease status.
Much of the knowledge for the signaling apparatus of MYD88 has been generated for wild-type MYD88. Knowledge of mutated Myddosome assembly and molecules involved in downstream signaling could help advance novel therapeutics. The creation of 3D-crystal structures of the mutated Myddosome, MYD88/IRAK complex, and MYD88/BTK complex can provide critical information for medicinal chemistry campaigns aimed at disrupting Myddosome assembly and signaling. Studies aimed at identifying signaling pathways associated with mutated MYD88 beyond BTK and IRAK, as well as identification of other pivotal scaffold and kinase nodal points in MYD88 signaling, are needed for advancing medicinal chemistry campaigns. The functional consequences of CXCR4 WHIM mutations are poorly understood. Both AKT and ERK are hyperactivated in response to the CXCR4 ligand CXCL12. Nevertheless, little else is known about the nature of CXCR4 mutations. Detailed signaling studies aimed at clarifying CXCR4 WHIM dysregulated signaling, including G-protein receptor transactivation, beta-arrestin and GRK recruitment, and impact on downstream growth and survival
signaling may help advance our understanding of the relevant biology and therapeutic exploitation in WM. Recent published clinical trial data on a small subset of WM patients treated with the BCL-2 inhibitor venetoclax look promising, and ibrutinib and venetoclax combinations are showing substantial responses in chronic lymphocytic leukemia. Additional understanding of the depth of response and potential resistance mechanisms to therapies that control the apoptotic pathways is needed.
Research to understand the biology of the immune response, in particular the anti- tumor immune response in WM, is vitally important, and clinical approaches to optimize the immune response need to be tested. Continued research characterizing the immune microenvironment in WM and an understanding of immune cell trafficking are needed. Specific knowledge gaps include understanding T effector cell exhaustion, determining the effect of immune checkpoint inhibitors, and defining the role of other immune cells, including NK cells and mast cells. Studies to identify high- risk WM patients who would most benefit from immune therapies, such as CAR T-cell therapy or immune checkpoint therapy, are needed.
- Bone Marrow/Tumor Microenvironment:
The role of the bone marrow and tumor microenvironment in supporting malignant cell growth and promoting resistance to therapy in WM requires additional focused research. Studies are required to better characterize the components of the tumor/bone marrow microenvironment in WM. A better understanding of the contribution of the microenvironment to disease progression (such as progression from IgM MGUS to WM) and resistance to treatment remains an important goal, as does an evaluation of the nature of the crosstalk between WM tumor cells and the associated microenvironment, including the effects of the stroma on immune cells. The development of a better model system of the bone marrow microenvironment to understand interactions between WM cells and the microenvironment is needed.
About The International Waldenstrom’s Macroglobulinemia Foundation (IWMF)
The IWMF is a patient-founded and volunteer-led, nonprofit organization that is dedicated to a simple but compelling vision: Support everyone affected by Waldenstrom's macroglobulinemia (WM) while advancing the search for a cure. The IWMF currently has a worldwide membership of over 15,000, with Support Groups and affiliate organizations on virtually every continent.
Today the IWMF:
- provides support to patients and their caregivers
- enables patients to communicate with one another
- sponsors patient educational forums about WM that feature prominent physicians and researchers
- publishes booklets and fact sheets on WM and its treatment
- supports research aimed at improving treatments and ultimately, finding a cure for WM
- has invested over $12.2 million dollars in research on WM since 1999
For more information, visit the IWMF website at http://www.iwmf.com.