Waldenström’s Macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) is a type of blood cancer that affects mostly elderly patients and has no curative options. Although ibrutinib - an inhibitor of Bruton’s tyrosine kinase (BTK) - has shown promise, a significant number of patients develop resistance to this drug.
To address this clinical need, researchers are exploring new treatment options, including venetoclax, an inhibitor of BCL-2 family proteins. These proteins normally suppress the death of cells and are often dysregulated in cancer, playing an important role in the pathogenesis of many blood cancers including WM/LPL. While good clinical results have been achieved with venetoclax for some patients, a significant subset of WM/LPL patients do not respond or only have a partial response, and prolonged treatment may lead to acquired resistance. Therefore, there is a need to identify novel targets and combination therapies.
“We think that the potential of venetoclax for the treatment of WM/LPL patients can be significantly improved by gaining better insight into the regulation and drug-resistance mechanisms of the BCL-2 protein family,” says principal investigator Dr. Marcel Spaargaren, Associate Professor at the Department of Pathology, Lymphoma and Myeloma Center Amsterdam (LYMMCARE), at Cancer Center Amsterdam (CCA).
Identifying Sensitizers
Supported by a grant from the International Waldenström's Macroglobulinemia Foundation (IWMF) - Leukemia & Lymphoma Society (LLS), Marcel and his research team plan to conduct functional genomic screens using CRISPR-Cas9 to identify potential sensitizers and perform in vitro and in vivo studies to determine their effectiveness.
“By identifying proteins involved in this process, we can potentially create new targeted combination therapies that could significantly improve the clinical efficacy of venetoclax and improve treatment options for patients with WM/LPL and possibly other B-cell malignancies,” says Dr. Spaargaren.
For more information, contact Marcel Spaargaren
Project title: Towards a rational targeted combination therapy for Waldenström’s Macroglobulinemia by venetoclax sensitizer CRISPR screens. Funded by the International Waldenström's Macroglobulinemia Foundation (IWMF) - Leukemia & Lymphoma Society (LLS), ($476.000).
This article was created forCancer Center Amsterdam.
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