Working with a master
NEW YORK—Working with and against the human immune system—in the cases of immunotherapies and immunological diseases—has long been recognized as a delicate balance. Researchers continue to seek therapies that can activate the immune system to target malignancies such as cancer cells without endangering healthy cells, or dial back the immune system's erroneous attack on healthy cells without crippling immune response as a whole—many diseases require therapeutics that step carefully, as it were.
Diffuse large B-cell lymphoma (DLBCL) is one such target. In this particular cancer, the lymphomas' survival hinges on Bc16, a master regulatory transcription factor that also plays a pivotal role in the healthy functioning of many immune cells. Due to its importance, Bc16 has generally been avoided as being too complex to target; while inhibiting Bc16 could serve to cripple the lymphomas, it also runs the risk of saddling patients with systemic inflammation and atherosclerosis. A team of researchers at Weill Cornell Medical College, however, have completed a study that reveals more about Bc16's functions, the risks associated with Bc16 inhibition and a way to shut down Bc16 in DLBCL that doesn't affect its function in T cells and macrophages.
Transcription factors' duties consist of either inhibiting or promoting the expression of genes, while master regulatory transcription factors such as Bc16 orchestrate the regulation of thousands of genes in a wide range of cells, making use of a variety of tools to control different cell types. Bc16 controls the type of immune cells that develops in bone marrow—which plays several roles in the development of B cells, T cells and macrophages, among others—and can also enable B cells to generate specific antibodies against pathogens. Dr. Ari Melnick, the study's lead investigator, explained Bc16's versatility by likening the transcription factor to a Swiss Army knife.
"In this analogy, the Swiss Army knife, or transcription factor, keeps most of its tools folded, opening only the one it needs in any given cell type. For B cells, it might open and use the knife tool; for T cells, the cork screw; for macrophages, the scissors. The amazing thing from a medical standpoint is that this means that you only need to prevent the master regulator from using certain tools to treat cancer," said Melnick in a press release. "You don't need to eliminate the whole knife. In fact, we show that taking out the whole knife is harmful since the transcription factor has many other vital functions that other cells in the body need."
The findings came about from preclinical testing of two Bc16-targeting agents developed Melnick and his team to treat DLBCLs: RI-BPI, a peptide mimic, and the small-molecule agent 79-6. Melnick is a hematologist-oncologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center, as well as Gebroe Family Professor of Hematology/Oncology and director of the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences at Weill Cornell.
DLBCL is the most common subtype of non-Hodgkin's lymphoma, and the seventh most frequently diagnosed type of cancer, and with the National Cancer Institute predicting 69,740 new cases of non-Hodgkin lymphoma in 2013 in the United States alone (and 19,020 deaths), new avenues for possible therapeutic approaches are welcome.
"Scientists have been searching for the right answer to treat this difficult lymphoma, which, after initial treatment, can be at high risk of relapse and resistant to current therapies," Melnick said in a press release. "Believing that Bcl6 could not be targeted, some researchers have been testing alternative therapeutic approaches. This study strongly supports the notion of using Bcl6-targeting drugs."
This discovery, Melnick noted, "means the drugs we have developed against Bcl6 are more likely to be significantly less toxic and safer for patients with this cancer than we realized."
In addition, it could also lead to new work in other diseases as well, as recent studies—from Melnick, amongst others—have shown that Bc16 also plays a role in some solid tumors and the most aggressive forms of acute leukemia. The revelation of Bc16 as having numerous functions that can be applied separately could allow researchers to target or inhibit certain of its "tools" depending on the disease and the desired result.
This study is the latest research from Weill Cornell into DLBCL this year. Melnick and his team announced the publishing of another study in January in Cancer Cell that detailed their work with MALT1, a protein that drives cancer cell growth in activated B cell-DLBCL.
Co-authors for this study, "Lineage-specific functions of Bcl-6 in immunity and inflammation are mediated by distinct biochemical mechanisms," include Drs. Chuanxin Huang and Katerina Chatzi from the Division of Hematology and Oncology at Weill Cornell Medical College. The study appeared in Nature Immunology.