Mantle cell lymphoma is an incurable form of non-Hodgkin lymphoma. Treatment is aimed at putting the disease into remission for the longest time possible. The disease, however, eventually returns. Accordingly, researchers are looking for novel therapies that will give patients a longer life expectancy.
B-cell non-Hodgkin lymphomas are often associated with dysregulation of a protein called B-cell lymphoma 2 (BCL-2) and its family of similar proteins. This protein family is involved in regulating programmed cell death (apoptosis) and includes pro-apoptosis and anti-apoptosis protein members. In B-cell non-Hodgkin lymphomas, the balance between these proteins is altered, leading to the disruption of apoptosis and the rogue survival of cancer cells.
Inhibiting the anti-apoptotic BCL-2 family proteins can switch the survival balance towards cell death and slow lymphoma progression and, for this reason, they have been the target of lymphoma treatments. One such inhibitor, venetoclax, is a highly specific inhibitor of BCL-2 and has FDA approval for use in leukemias. In early clinical trials, venetoclax shows promising results for mantle cell lymphoma as well. However, a significant subset of mantle cell lymphoma patients are — or become — resistant after prolonged venetoclax treatment.
Understanding the limitation of venetoclax
Dr. Marcel Spaargaren, PhD student Yvonne Thus, and Cancer Center Amsterdam colleagues Prof. Eric Eldering and Prof. Arnon Kater, recently published a review in the journal Leukemia outlining the development of inhibitors, including venetoclax, for specific BCL-2 family proteins.
“Patients relapse because high levels of other BCL-2 related anti-apoptotic proteins, namely myeloid cell leukemia-1 (MCL-1) and/or B-cell lymphoma-extra large (BCL-XL), stand in for BCL-2 when it is inhibited,” says Dr. Spaargaren. These ‘stand-ins’ are even upregulated after prolonged venetoclax treatment.
Dr. Spaargaren surmises that inhibiting these family members in addition to BCL-2 might overcome the venetoclax resistance in mantle cell lymphoma.
Looking beyond venetoclax
Several studies are already trialling venetoclax in combination with other drugs, the most promising to date being the Bruton's tyrosine kinase inhibitor ibrutinib. To expand the search for new therapies, Dr. Spaargaren and his team screened kinases for potential new targets that can overcome resistance against venetoclax. The team used a functional genomic CRISPR-Cas9 knockout sensitizer screen, a powerful technique for identifying new drug targets.
In their newly published research article in Haematologica, Dr. Spaargaren, PhD student Thus, and their team report that the screening identified casein kinase 2 (CK2) as a major determinant of venetoclax sensitivity. “In fact, we also found that CK2 is overexpressed in mantle cell lymphoma and high CK2 expression is associated with poor patient survival,” Dr. Spaargaren explains. However, treatment targeting CK2 alone was not effective in killing mantle cell lymphoma, either through CK2 knockdown (mediated by RNA interference) or by using the CK2-inhibitor, silmitasertib.
Better together
Next, the team tried combining silmitasertib with venetoclax. The effect was strongly synergistic. “Together, these two drugs result in enhanced BCL-2 dependence for cancer cell survival and, consequently, venetoclax effectiveness,” says Dr. Spaargaren. “Our findings indicate that targeting of CK2 sensitizes mantle cell lymphoma to venetoclax through downregulation of MCL-1.”
These insights provide a strong rationale for combining venetoclax with the CK2-inhibition drug, silmitasertib, as therapeutic strategy for mantle cell lymphoma patients. Further trials are planned to investigate if this combination is safe and effective for the treatment of patients with mantle cell lymphoma.
Read the review article in Leukemia here:
Read the research article in Haematologica here:
For more information, contact: Marcel Spaargaren.
Researchers affiliated with Cancer Center Amsterdam
Yvonne J. Thus
Martin F.M. de Rooij
Nathalie Swier
Jeroen E.J. Guikema
Eric Eldering
Steven T. Pals
Arnon P. Kater
Marcel Spaargaren
Funding
This research was supported by grants from the Dutch Cancer Society (KWF) and the Lymph&Co foundation to Marcel Spaargaren.
Text by Lynita Howie.
This article was created for Cancer Center Amsterdam.
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