Research findings were published online in Science Translational Medicine.
The study, led by Michael Green, Ph.D., assistant professor of Lymphoma & Myeloma, showed that transcription factor 4 (TCF4) is the most frequent genetic alteration in activated B-cell-like diffuse large B-cell lymphoma (ABC-like DLBCL), and may be amenable to therapeutic targeting with bromodomain-inhibiting drugs called BET-inhibitors.
DLBCL is the most common form of lymphoma and is treatable in 60% of patients using a combination chemotherapy and immunotherapy regimen, R-CHOP. The subtype ABC-like DLBCL is associated with substantially worse outcomes for patients when first-line therapy fails.
Improving lymphoma treatment
“DLBCL can be successfully treated, but therapies are needed for those who relapse, or are refractory to current treatments,” said Green. “Our team found that a percentage of ABC-like DLBCL patient tumors had copy gains on part of chromosome 18, which increased TCF4 expression, which in turn, activated immunoglobulin M (IgM) and MYC. These findings suggest that targeting TCF4 may hold promise against ABC-like DLBCL.”
A common avenue for tumorigenesis is the gain or loss of DNA encoding oncogenes or tumor suppressor genes. Green’s team found that tumors with chromosome 18 gains were dependent on TCF4 and that TCF4 was regulated by bromodomain protein BRD4. They then tested bromodomain inhibition in xenograft mouse models and reported reduced tumor growth and enhanced survival.
The scientists determined that reduction of TCF4 is one of the mechanisms by which BET inhibition reduces IgM and MYC expression and induces apoptosis in ABC-like DLBCL cells with TCF4 DNA copy number gain.
In particular, Green looked at ARV771, a BET degrader, and found that tumors were significantly smaller in ARV-771-treated mice, with reduced levels of BRD4, TCF4, IgM and MYC expression. Their findings demonstrated that the molecule could reach the tumor site in sufficient concentration to have a functional effect.
“There were no signs of toxicity within these mice, and treatment with ARV771 was associated with a significant prolongation of their survival,” said Green. “Our data provide a clear rationale for BET inhibition in ABC-like DLBCL and show that ARV771 is effective at eliminating TCF4 and its target genes and treating ABC-like DLBCL cell lines in vitro and in vivo. These findings highlight a novel genetic basis for this type of lymphoma with potential implications for future clinical studies.”