1. DiGiulio, Sarah

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Bromodomain-containing protein-4 (BRD4) has been shown in previous research to play a role in oncogenic transcription in multiple myeloma, as well as diffuse large B-cell lymphoma (DLBCL)-and new findings suggest BRD4 also plays a role in regulating the oncogenic drivers in CTCL and that the BRD4 inhibitor JQ1 might reverse that process, according to a study presented during an oral session at the American Society of Hematology Annual Meeting (Abstract 589).

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"BET family proteins, such as BRD4, have never been explored in CTCL patients. This is the first report identifying abnormal occupancy patterns of BRD4 in CTCL genome in patient's cells," one of the study's corresponding authors, Pierluigi Porcu, MD, Professor of Medicine in the Division of Hematology at Ohio State University Comprehensive Cancer Center, said in an email after the meeting.


"BRD4 occupancy in the CTCL genome was highest at well-known cancer driving genes, such as MYC, NOTCH1, and RBPJ.


"These findings suggest that BRD4 regulates major oncogenic pathways in CTCL that can be reversed using BRD4 inhibitors such as JQ1."


The researchers designed the study to identify the role of BRD4 in the CTCL genome and downstream oncogenic pathways, as well as to investigate the effect of treatment with the BRD4 inhibitor JQ1 on CTCL. They created a genome-wide map of BRD4 occupancy in CD4-positive T-cells from patients with CTCL, as well as from healthy donors using chromatin immunoprecipitation (ChIP) with sequencing of BRD4-associated DNA.


The resulting analysis showed higher levels of BRD4 occupancy in the T-cells of patients with CTCL compared with those from healthy donors at putative active regions, promoter active regions, distal active regions, and super-enhancers. BRD4 levels were also found to be higher at the NOTCH1 and MYC pathways in the cells from the patients with CTCL, compared with the cells from the healthy donors. And, BRD4 levels were found to be elevated at the DNA-binding factor gene RBPJ, known to be an activator of NOTCH1, as well as a T-cell oncogenic co-factor.


The team also used the HuT78 cell line-originally derived from the peripheral blood of a patient with a leukemic variant of CTCL-to validate the findings that BRD4 occupancy was also highest at the MYC, NOTCH1, and RBPJ cancer driving genes in that cell line, too, Porcu said.


Additionally, the results showed that when treated with the BRD4 inhibitor JQ1, those abnormal binding patterns of BRD4 in the malignant cells were reversed. And, in vivo treatment in mice with CTCL with JQ1 stopped and regressed progression of the disease in the mice.


Clinical Trials

Bromodomain inhibitors are currently in Phase I clinical trials in a variety of hematologic malignancies, such as lymphoma, leukemia, and myeloma, as well as in some solid tumors, Porcu noted; no bromodomain inhibitor is currently approved in the U.S. for cancer therapy, though.


Preliminary data suggest a good safety profile without major non-hematologic toxicity; and based on clinical responses seen in some of the trials (namely lymphomas), it is expected that one or more of these drugs will proceed to Phase II studies, he said.


A very small number of patients with CTCL have been enrolled in Phase I clinical trials for bromodomain inhibitors, but it is too early to say if the drugs are clinically active in CTCL or will proceed to Phase II trials for the disease. But, he said: "If the response rate in CTCL is encouraging-at least 30 percent-our laboratory work will focus on understanding the mechanisms of response and resistance to these drugs, based on the patterns of genome-wide BRD4 protein binding in sensitive versus resistant cells, and on how to combine them with other epigenetic drugs currently approved for CTCL, such as the HDAC inhibitors romidepsin and vorinostat."


The other researchers were Anjali Mishra, PhD (first author); Alex Hartlage; Laura Sullivan; Leah Grinshpun; Sonya Kwiatkowski; Jun Qi; PhD3; James E. Bradner, MD; and Michael A. Caligiuri, MD.