Preclinical research has shown that mantle cell lymphoma is so critically dependent on the FOXO1 protein that by blocking its activity with an experimental drug, the cancer’s growth may be slowed, according to a new study published by Jang et al in the Journal of Clinical Investigation. Investigators believe the discovery may lead to new mantle cell lymphoma therapies as well as a better understanding of how this type of lymphoma develops.
“There’s a strong need for better therapies against mantle cell lymphoma, and our findings suggest that inhibition of [the FOXO1] protein could be an effective new strategy to try alone or in combination with existing drugs,” said co–senior study author Jihye Paik, PhD, Associate Professor of Pathology and Laboratory Medicine at Weill Cornell Medical College.
Relatively rare—with only about 2,000 new cases per year in the United States—most cases of mantle cell lymphoma are diagnosed in male patients aged 60 to 80 years. The disease is known for its slow progression, but it generally recurs after therapy, and is considered virtually incurable.
Transcription Factor Protein Targets
In this new study, the researchers used CRISPR/Cas9 gene-editing technology on arrays of mantle cell lymphoma cells grown in the laboratory to block 1,427 different transcription factor proteins. Many cancers depend on the activities of particular transcription factor proteins, although traditionally they have been hard to target with drugs.
The screening process revealed several transcription factor proteins whose disruption caused a severe slowdown in mantle cell lymphoma cell division, without slowing the growth of other cell types. The researchers further discovered that the FOXO1 transcription factor protein was responsible for driving the activities of the others—and essentially worked as a critical factor sustaining the pattern of gene activity characteristic of mantle cell lymphoma cells.
The researchers—in collaboration with biotechnology company Forkhead Biotherapeutics, which had been developing FOXO1-inhibiting compounds for the potential treatment of type 1 diabetes—found that using FOXO1 inhibitors resulted in similar effects on mantle cell lymphoma cells as blocking the FOXO1 protein by genetic means. The compound also significantly extended survival in a mouse model of mantle cell lymphoma.
Critical to the development of some normal cell types, the FOXO1 protein has been found to suppress, rather than promote, some other cancers in prior studies. Yet, in this study, adult mice tolerated a month of FOXO1-inhibitor treatment with no major side effects.
Looking Ahead
“This has the potential to be a relatively safe strategy for treating mantle cell lymphoma,” said co–senior study author Hongwu Zheng, PhD, Assistant Professor of Research in Pathology and Laboratory Medicine at Weill Cornell Medical College.
The researchers plan to continue their preclinical investigations by further optimizing FOXO1 inhibitors and looking for a suitable combination with other medications for more potent and durable responses.
Disclosure: For full disclosures of the study authors, visit jci.org.
