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.
Scientific Synopsis
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.
(A) Results of the HTS screening: Log10 molar IC50 plots comparing Cal-1 and Gen2.2 BPDCN cell lines. Of the 1,910 compounds screened, 314 showed activity in both BPDCN lines, after excluding inactive and poorly fitting compounds. BETis are highlighted in red. (B) Toxicity of BRD4 and TCF4 shRNAs in BPDCN cell lines. Shown is the fraction of live, shRNA-expressing (GFP+) cells over time after shRNA induction, compared with the day-0 uninduced value. (C) BPDCN cells were treated with either DMSO or the indicated amount of BETi JQ1. Cell viability was assessed by MTS assay at day 3 after treatment. (D) BPDCN cells were treated with either DMSO or the indicated amount of JQ1. The percentage of apoptotic cells (active caspase-3+, cleaved Parp1+) is shown at day 1 and day 2 after treatment. (E) BPDCN xenograft models were established by subcutaneous injection of Cal-1 and Gen2.2 cells in NOD/SCID mice and treated with either vehicle or the BETi CPI 203 (5 mg/kg) for the indicated time points. Tumor growth was measured as a function of tumor volume. (F) Relative mRNA levels of TCF4 and three of its targets in Cal-1 xenografts from mice treated for 5 days with CPI 203 or vehicle control. (Reprinted with permission from Ceribelli, M., et al. A Druggable TCF4 and BRD4 dependent Transcriptional Network Sustains Malignancy in Blastic Plasmacytoid Dendritic Cell Neoplasm. Cancer Cell, 30(5), 764–778. Copyright 2016 Cancer Cell.)
Lead Collaborators
- 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
Publications
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.
Outcomes
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.