Scientists based at Icahn School of Medicine at Mount Sinai have discovered a new class of drugs that they think has potential to treat a subtype of non-Hodgkin’s lymphoma—mantle cell lymphoma—that is normally fatal.
The drug candidates are small molecules that inhibit the action of the SOX11 oncogene and in the lab have shown the ability to stop mantle cell lymphoma development.
Mantle cell lymphoma comprises about 6% of all non-Hodgkin’s lymphoma cases and has a 5-year survival of around 50%. It does not currently have a clear ‘standard’ treatment and patients tend to receive one or a combination of chemotherapy, immunotherapy (including CAR-T cell therapy), or targeted Bruton tyrosine kinase inhibitors. Although there are some treatments available, patients commonly relapse and there is an unmet need for more effective therapies.
A barrier to developing effective treatments for this kind of cancer has been targeting the transcription factor SOX11, which is highly expressed in mantle cell lymphoma, as it was previously considered ‘undruggable’ by drug developers. However, Samir Parekh, a professor at the Icahn School of Medicine, and colleagues sought to prove otherwise.
“The SOX 11 protein, which is expressed in up to 90% of mantle cell lymphoma patients, is an attractive target for therapy, 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, actually kill lymphoma cells with remarkable efficiency,” he explained in a press statement.
The research team screened more than 12 million compounds for their ability to target the SOX11 protein and managed to identify a few compounds with the ability to block SOX11 activity. Of these, three were tested in the lab and their inhibitory action was confirmed.
One showed more significant anti-cancer action than the other two and seemed to boost the effects of the Bruton tyrosine kinase inhibitor ibrutinib, often given to patients with mantle cell lymphoma, including in SOX11 positive ibrutinib-resistant patient samples. In a mouse model with a cancer patient-derived xenograft, this candidate drug also blocked Bruton tyrosine kinase phosphorylation, which is thought to play a role in this kind of cancer.
The research team now plans to develop this drug candidate further and also to explore whether this new drug class could be useful for treating other cancers.
“These novel small molecule inhibitors will also be useful for understanding the pathogenesis of other SOX11 positive malignancies such as epithelial ovarian tumors, medulloblastoma, gliomas and basal like breast cancer, and ultimately expand therapeutic options for SOX11-expressing human cancers,” write the authors in the journal Clinical Cancer Research.