Towards a rational targeted therapy for Waldenstrom's Macroglobulinemia by kinome-centered loss-of-adhesion and synthetic lethality screens
Marcel Spaargaren
PhDAcademic Medical Center Amsterdam
Project Term: March 1, 2020 - March 1, 2022
We have previously demonstrated that disrupted retention of the malignant B cells within lymphoid organs is a key mechanism of action of the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, underlying its unprecedented high clinical efficacy in the treatment of chronic lymphocytic leukemia, mantle cell lymphoma and Waldenström’s Macroglobulinemia (WM). Unfortunately, apart from innate (primary) resistance, a significant subset of patients who receive prolonged treatment with ibrutinib develop (secondary) therapy resistance. Considering microenvironment-dependence as the Achilles’ heel of WM cells, we hypothesize that induction of homelessness by targeting localization (homing and retention) as well as survival/proliferation of WM cells in their lymphoid organ microenvironment by combination therapy may overcome innate (primary) resistance and prevent acquired (secondary) drug-resistance, providing a powerful strategy to cure WM. Therefore, our aims are: 1) to identify the signaling pathways and kinases (given their druggability) that control WM cell retention and outgrowth; 2) to identify kinases whose inhibition sensitizes WM cells to the anti-adhesive and growth-inhibitory effects of ibrutinib, and 3) to explore and exploit their potential as therapeutic targets for development of novel targeted (combination) therapy for WM patients.
The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib is the first-ever FDA- and EMA-approved treatment for patients with Waldenström’s Macroglobulinemia (WM), a B-cell malignancy. Previously, we have identified BTK as a critical mediator of adhesion (retention) in and migration (homing) of B cells into lymphoid organs. Moreover, we have demonstrated that disrupted retention within and homing into lymphoid organs is a key mechanism of action of ibrutinib, underlying its unprecedentedly high efficacy as monotherapy in the treatment of relapsed/refractory chronic lymphocytic leukemia, mantle cell lymphoma and WM. Ibrutinib causes a rapid redistribution of malignant lymphocytes from the lymph nodes (and bone marrow) to the blood, giving rise to a treatment-characteristic transient increase in lymphocytosis. This mobilization into the blood deprives the malignant cells of essential growth and survival factors provided by the lymphoid microenvironment, resulting in highly efficacious lymphoma regression. In general, these findings suggest that (signaling) molecules underlying the control of homing and retention are potential prime targets for lymphoma treatment. Unfortunately, apart from primary resistance, a significant subset of patients who receive prolonged treatment with ibrutinib develop secondary resistance due to recurrent mutations of BTK, resulting in a poor clinical outcome. Thus, there is an urgent clinical need for the identification of novel targets and development of novel (combination) therapy, which may be more effective and can prevent or overcome therapy resistance. We hypothesize that induction of homelessness by targeting homing and retention in the lymphoid organ microenvironment may be a powerful general strategy to cure WM. Furthermore, considering the microenvironment-dependence as the Achilles’ heel of WM cells, we hypothesize that targeting both localization (homing and retention) and survival/proliferation of WM cells in their lymphoid organ microenvironment by combination therapy would provide a highly efficacious treatment, due to an improved efficacy/toxicity ratio and the capacity to overcome innate (primary) resistance and prevent acquired (secondary) drug-resistance. Therefore, our aims are: 1) to identify the signaling pathways and kinases (given their druggability) that control WM cell homing, retention and outgrowth; 2) to identify kinases whose inhibition sensitizes WM cells to the anti-adhesive and growth-inhibitory effects of ibrutinib, and 3) to explore and exploit their potential as therapeutic targets for development of novel targeted (combination) therapy for WM patients.