Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive and largely incurable hematologic malignancy originating from neoplastic transformation of plasmacytoid dendritic cells (pDCs). Although an initial response to chemotherapy is common, BPDCN prognosis is extremely poor, and most patients relapse into a drug-resistant disease, highlighting the need for new treatment strategies.
To identify novel therapeutic options for BPDCN, researchers in the Chemical Technology group at NCATS performed a high-throughput single agent drug screening in two different BPDCN cell lines.
By focusing only on drugs that were active in both models, NCATS researchers discovered that several bromodomain and extra-terminal domain inhibitors (BETis) were highly toxic to BPDCN. Mechanistically, BETi-induced apoptosis in BPDCN takes place via the disruption of a BPDCN-specific transcriptional network controlled by pDC-restricted master transcriptional regulator TCF4.
To expand these findings in vivo, NCATS researchers established BPDCN xenografts by subcutaneous injection of BPDCN cell lines into non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. Treatment with the BETi CPI 203 was effective as a single agent in reducing tumor growth in both BPDCN xenograft models, supporting the clinical evaluation of BETis in this recalcitrant malignancy.
The results of this study were published in Cancer Cell in November 2016.
- Louis, M. Staudt, MD, PhD, NCI, NIH
- Craig J. Thomas, PhD, NCATS, NIH
- Boris Reizis, PhD, Columbia University Medical Center
- Michele Ceribelli, PhD, NCATS NIH
Ceribelli, M., Hou, Z. E., Kelly, P. N., Huang, D. W., Wright, G., Ganapathi, K., Evbuomwan, M.O., Pittaluga,S., Shaffer,A.L., Marcucci,G., Forman, S.J., Xiao, W., Guha, R., Zhang,X., Ferrer, M., Chaperot, L., Plumas, J., Jaffe, E.S., Thomas, C.J., Reizis, B., Staudt, L. M. (2016). A Druggable TCF4 and BRD4 dependent Transcriptional Network Sustains Malignancy in Blastic Plasmacytoid Dendritic Cell Neoplasm. Cancer Cell, 30(5), 764–778. http://doi.org/10.1016/j.ccell.2016.10.002
Public Health Impact
Bromodomain and extra-terminal domain inhibitors may represent a new class of agents used to treat blastic plasmacytoid dendritic cell neoplasms that are resistant to current chemotherapy.
This study provides a mechanistic rational for the clinical evaluation of bromodomain and extra-terminal domain inhibitors as a novel strategy to treat blastic plasmacytoid dendritic cell neoplasm.