The discovery could lead to new drugs against mantle cell lymphoma

The discovery could lead to new drugs against mantle cell lymphoma

A form of blood cancer known as mantle cell lymphoma is critically dependent on a protein that coordinates gene expression, so blocking its activity with an experimental drug dramatically slowed the growth of this lymphoma in preclinical tests, according to a study by researchers at Weill Cornell Medicine.

The discovery, reported Oct. 25 in the Journal of Clinical Investigation, could lead to new drugs for mantle cell lymphoma as well as a better understanding of how this type of lymphoma develops.

There is a strong need for better treatments for mantle cell lymphoma, and our results suggest that inhibiting this protein, called FOXO1, could be an effective new strategy that could be tried alone or in combination with existing drugs.”

Dr. Jihye Paik, co-senior author, associate professor of pathology and laboratory medicine and member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine

Lymphomas are cancers that arise in lymph nodes, small organs where immune cells gather to intercept infectious pathogens. Mantle cell lymphomas (MCLs) arise from immune cells called B cells that produce antibodies in areas of lymph nodes known as “mantle zones.” Most cases are diagnosed in men in their 60s or 70s. MCL is relatively rare, with only about 2,000 new cases per year in the United States, and it often progresses slowly, but it generally recurs after therapy and is considered virtually incurable.

In the study, researchers used CRISPR/Cas9 gene editing technology on arrays of MCL cells grown in the lab to block 1,427 different transcription factor proteins. Transcription factors are proteins that bind to DNA and act as master programmers of gene activity. Many cancers depend on the activity of certain transcription factors, although they have traditionally been difficult to combat with drugs.

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The screening process revealed several transcription factors whose disruption caused a strong slowdown in MCL cell division without slowing the growth of other cell types. The researchers discovered in further experiments that one of them, FOX01, is responsible for driving the activities of the others - essentially acting as a critical factor that maintains the pattern of gene activity that defines MCL cells.

Dr. Paik and Zheng soon contacted scientists at a biotechnology company, Forkhead Biotherapeutics, which has been trying to develop FOX01-inhibiting compounds for possible use in treating type 1 diabetes. Using an experimental FOX01 inhibitor from the company, researchers found that it had similar effects on MCL cells as genetically blocking FOX01. The compound also significantly prolonged survival in a mouse model of MCL.

FOX01 is crucial for the development of some normal cell types. Previous studies have also found evidence that FOX01 helps suppress, rather than promote, some other cancers. But in this study, adult mice tolerated treatment with the FOX01 inhibitor for a month without any major side effects.

“This has the potential to be a relatively safe strategy for treating MCL,” said Dr. Hongwu Zheng, the study's other co-author and assistant professor of research in pathology and laboratory medicine at Weill Cornell Medicine.

The researchers plan to continue their preclinical studies by further optimizing the FOXO1 inhibitors and looking for an appropriate combination with other drugs for stronger and more durable responses.

Source:

Weill-Cornell medicine

Reference:

Jang, J.Y., et al. (2022) A FOXO1-dependent transcriptional network is a targeted vulnerability of mantle cell lymphomas. Journal of Clinical Investigation. doi.org/10.1172/JCI160767.

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