The small-molecule inhibitors of the SOX 11 oncogene showed promise both as single agents and in combination with ibrutinib.
A new class of drugs, small-molecule inhibitors of the SOX 11 oncogene, could inhibit a “master switch” involved in most cases of mantle cell lymphoma (MCL), according to researchers at Mount Sinai Hospital.
A new in vitro study has found that the drugs are toxic to MCL tumor development in human cells. If this effect is replicated in living patients, the researchers said the discovery could lead to new therapies for the highly resistant disease.
MCL represents approximately 6% of all cases of non-Hodgkin lymphoma, which itself is the most common hematological malignancy. Although significant advances have been made with chemotherapies and immunotherapies, patients with MCL have a median survival of 7 to 8 years, and continually relapse.
One obstacle to the development of treatments overcoming this cellular resistance has been the fact that SOX 11 is generally considered “undruggable,” according to the study. SOX 11 is a transcription factor that binds to DNA and acts as a master switch to turn genes off and on.
“The SOX 11 protein, which is expressed in up to 90% of mantle cell lymphoma patients, is an attractive target for therapy,” said senior author Samir Parekh, MD, a professor in the Icahn School of Medicine at Mount Sinai, in a press release. “But until now, no small-molecule inhibitor had been identified. We discovered 3 structurally related compounds which are able to bind to the oncogene, perturb its interaction with DNA and, through their anti-[mantle cell lymphoma] cytotoxicity, actually kill lymphoma cells with remarkable efficiency.”
In an effort to prove that SOX 11 is not undruggable, Parekh and his colleagues screened more than 12 million compounds at the SOX 11 surface that interact with DNA. They identified several small molecules that were predicted to perturb the interaction of SOX 11 with DNA, thereby blocking the mechanism allowing MCL to develop.
Experimental validation confirmed that 3 of these molecules inhibited the SOX 11-DNA interaction. Notably, one molecule showed anti-MCL cytotoxicity and inhibition of phosphorylation of BTK, which the researchers said is part of a signaling cascade that triggers the malignant transformation of B lymphocyte cells into MCL.
The molecules showed efficacy as single agents, and the research also showed promise for ibrutinib in combination with a SOX 11 inhibitor. Either of these approaches could represent a new therapeutic strategy for treating MCL, according to the study authors.
“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 tumors, medulloblastoma, gliomas, and basal-like breast cancer,” Parekh said in the press release. “Many transcription factors exist in a variety of tumors 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.”
Researchers discover a novel class of drugs that may help treat a deadly type of lymphoma. News release. EurekAlert. June 22, 2021. Accessed June 23, 2021. https://www.eurekalert.org/pub_releases/2021-06/tmsh-rda062121.php