James E. Bradner, M.D. Christopher A. French, M.D.
Dana-Farber Cancer Institute Brigham and Women's Hospital

Reprogramming the Tumor Epigenome in NUT Midline Carcinoma

NUT midline carcinoma is carcinoma genetically defined by the fusion of two genes, the NUT gene and the BRD4 gene. The organs in our bodies are formed from progenitor cells, similar to stem cells, which differentiate to form functioning mature cells specific to an organ. Without differentiation into specialized cells, the progenitor cells can continue to grow. When the BRD4-NUT gene is present, the progenitor cells cannot mature into their specialized cell types, thus they continue to grow and form cancerous tumors. This happens because when this gene associates with cellular DNA, it blocks the transcription of genes that encode the proteins required for cell differentiation.

Drs. French and Bradner propose the use of HDAC inhibitor drugs to biochemically alter the structure of DNA in such a way as to disrupt the pattern of BRD4-NUT-DNA association that leads to its inhibition of gene transcription. These drugs will be capable of increasing the levels of transcriptional activity and allow essential genes, such as the maturation genes that the BRD4-NUT blocks, to be transcribed and expressed. The use of these drugs will be able to activate differentiation of NUT midline carcinoma cells and essentially convert them back into normal cells. The researchers applied differentiation therapy in a patient setting, which demonstrated a clinical response. This is the first example of using differentiation therapy in a solid tumor. The researchers are developing new HDAC inhibitors to be more effective in differentiation therapy.