Researchers discover class of drugs that could treat mantle cell lymphoma
A screening campaign has revealed that small molecule inhibitors of the SOX 11 oncogene are toxic to mantle cell lymphoma in vitro.
A new class of small molecule drugs that inhibits a “master switch” involved in the vast majority of cases of mantle cell lymphoma (MCL), a fatal subtype of non-Hodgkin’s lymphoma, has been discovered via screening by researchers at the Mount Sinai Hospital and Mount Sinai School of Medicine, US.
The team reported that the drugs, inhibitors of the SOX 11 oncogene, are toxic to MCL tumour development in human cells studied outside the body. According to the researchers, if the effect is replicated in living patients, the discovery could lead to new therapies for a disease that is highly resistant to existing treatments.
“The SOX 11 protein, which is expressed in up to 90 percent of mantle cell lymphoma patients, is an attractive target for therapy,” said senior author Professor Samir Parekh. “But until now, no small molecule inhibitor had been identified. We discovered three structurally related compounds which are able to bind to the oncogene, perturb its interaction with DNA and through their anti-MCL cytotoxicity, kill lymphoma cells with remarkable efficiency.”
After screening more than 12 million compounds at the SOX 11 surface that interact with DNA, the team identified a number of small molecules that were predicted to perturb the SOX 11-DNA interaction, thereby blocking the mechanism by which mantle cell lymphoma develops.
Experimental validation confirmed the inhibitory role of three of these molecules. One in particular showed in in vitro laboratory studies anti-MCL cytotoxicity and inhibition of phosphorylation of BTK, which is part of a signalling cascade that triggers the malignant transformation of B lymphocyte cells into MCL. The researchers showed the efficacy of the molecules as single agents, as well as the synergy of ibrutinib in combination with a SOX 11 inhibitor – either of which could potentially represent a therapeutic strategy for treating MCL.
“These small molecule inhibitors could also be useful tools for understanding the pathogenesis of other malignancies that can be traced to SOX 11, including epithelial ovarian tumours, medulloblastoma, gliomas and basal-like breast cancer,” said Parekh. “Many transcription factors exist in a variety of tumours that could be targeted by scientists, and what we’ve demonstrated through our work is that there is indeed an effective way to make them druggable.”
The study is published in Clinical Cancer Research.