Unique Class Of Medicines That Aid In Treatment Of Lymphoma

Unique Class Of Medicines That Aid In Treatment Of Lymphoma

Mount Sinai researchers have found a novel family of medicines that disrupt a master switch implicated in the vast majority of instances of mantle cell lymphoma (MCL), a deadly subtype of non-Hodgkin’s lymphoma.

Unique Class Of Medicines That Aid In Treatment Of Lymphoma

The medicines, known as small-molecule inhibitors of the SOX 11 oncogene, are hazardous to MCL tumor growth in human cells tested outside the body, according to a study published in Clinical Cancer Research in June. If the impact is duplicated in real patients, the discovery might lead to novel medicines for a condition that is resistant to current treatments.

Unique Class Of Medicines That Aid In Treatment Of Lymphoma

According to lead author Samir Parekh, MD, Professor of Medicine (Hematology and Medical Oncology), Icahn School of Medicine at Mount Sinai, the SOX 11 protein, which is expressed in up to 90% of mantle cell lymphoma patients, is an appealing target for treatment. 

However, no small-molecule inhibitor had been discovered till recently. They found three structurally similar chemicals that can attach to the oncogene, disrupt its connection with DNA, and kill lymphoma cells with exceptional efficiency via anti-MCL cytotoxicity.

Mantle cell lymphoma accounts for roughly 6% of all instances of non-lymphoma-Hodgkin’s the most prevalent hematological cancer in the world. Despite improvements in chemotherapy and immunotherapy, MCL patients have a median lifespan of seven to eight years and relapse following treatments such as ibrutinib, a small-molecule second-line treatment for the disease. 

The fact that SOX 11–a transcription factor that binds to DNA and functions as a master switch to turn genes on and off—is widely thought to be unbreakable has been a major impediment to the discovery of chemicals that may overcome cellular resistance to therapy.

Dr. Parekh initiated a collaboration with major Mount Sinai research laboratories in Pharmacological Sciences and Oncological Sciences, as well as the Mount Sinai Center for Therapeutics Discovery, specializing in structural biology, computer-aided drug discovery, and medicinal chemistry, and led respectively by Aneel Aggarwal, Ph.D., Marta Filizola, Ph.D., and Jian Jin, Ph.D., to demonstrate otherwise. 

The researchers discovered several small chemicals that were expected to disturb the SOX 11-DNA connection, therefore inhibiting the process through which mantle cell lymphoma develops after screening more than 12 million compounds at the SOX 11 surface that interact with DNA.

Three of these compounds’ inhibitory function was validated by experimental confirmation. One, in particular, demonstrated anti-MCL cytotoxicity and suppression of phosphorylation of BTK in ex vivo laboratory tests on human cells outside the body, which is part of a signaling cascade that causes the malignant transition of B lymphocyte cells into mantle cell lymphoma. 

The Mount Sinai study demonstrated the effectiveness of the compounds as single agents as well as the synergy of ibrutinib in combination with a SOX 11 inhibitor—either of which might constitute a treatment approach for MCL.

According to Dr. Parekh, these small molecule inhibitors might also be valuable tools for studying the etiology of various malignancies linked to SOX 11, such as epithelial ovarian tumors, medulloblastoma, gliomas, and basal-like breast cancer. In a larger sense, he hopes that his team’s discoveries will inspire others to do new research into transcription factors such as SOX 11. 

Many transcription factors exist in a range of cancers that scientists might target, and their research has shown that there is an effective approach to make them druggable.

The collaboration with Ohio State University and the National Institutes of Health as part of the Mount Sinai-led project was made possible by funding and research collaboration of major academic institutions dedicated to expediting the discovery and development of new cancer treatments and diagnostics.

The Tisch Cancer Institute at Mount Sinai is part of this collaboration, which is supported by Celgene Corporation, as are cancer institutes at the University of Pennsylvania, Columbia University, and Johns Hopkins University.


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