One form of leukemia known as mantle cell lymphoma is so critically dependent on a protein that orchestrates gene expression that blocking its activity with an experimental drug significantly slowed lymphoma growth in preclinical tests, according to a study by Weill Cornell Medicine researchers. .
The discovery was made on October 25th Journal of Clinical Investigationcould lead to new drugs for mantle cell lymphoma as well as a better understanding of how this type of lymphoma develops.
Better therapies against mantle cell lymphoma are urgently needed, and our findings suggest that inhibiting this protein, called FOXO1, could be an effective new strategy to try alone or in combination with existing drugs.”
Dr. Jehi Paik, co-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 the lymph nodes, which are small organs where immune cells gather to intercept infectious pathogens. Mantle cell lymphomas (MCLs) arise from immune cells called B cells, which make antibodies, in areas of lymph nodes known as “mantle areas.” 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, often develops slowly, but generally recurs after treatment, and is considered nearly incurable.
In this study, the 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 types of cancer depend on the activities of specific transcription factors, although they have traditionally been difficult to target with drugs.
Screening revealed several transcription factors whose inactivation causes a severe slowdown in MCL cell division, without slowing the growth of other cell types. In further experiments, researchers discovered that one of them, FOX01, is responsible for driving the activities of the others – and essentially acts as a critical factor in maintaining the pattern of gene activity that defines MCL cells.
Dr.. Paik and Cheng soon reached out to scientists at a biotech company, Forkhead Biotherapeutics, which was trying to develop FOX01-inhibiting compounds for potential use in treating type 1 diabetes. Using an experimental FOX01 inhibitor from the company, the researchers found that it had similar effects on MCL cells as blocking FOX01 by genetic means. The compound also significantly prolonged survival in a mouse model of MCL.
FOX01 is critical for the development of some normal cell types. Previous studies have also found evidence that FOX01 helps suppress, rather than promote, some other types of cancer. However, in this study, adult mice tolerated a month of treatment with the FOX01 inhibitor without any significant side effects.
“This is likely to be a relatively safe strategy for treating MCL,” said Dr. Hongwu Zheng, the study’s other co-lead author and assistant professor of pathology and laboratory medicine at Weill Cornell Medicine.
The researchers plan to continue their preclinical investigations by further optimizing FOXO1 inhibitors and searching for a suitable combination with other drugs for more effective and lasting responses.
Jang, J.; et al. (2022) The FOXO1-dependent transcriptional network is a weak target of mantle cell lymphomas. Journal of Clinical Investigation. doi.org/10.1172/JCI160767.