Scientists identify a roadmap to 'cancer dependencies' in lymph node cancer


Blocking lymphoma cells' growth controls seen as potential treatment strategy

James Bradner, MDJames Bradner, MD

Scientists at Dana-Farber Cancer Institute used an experimental drug to block vulnerable cell growth pathways in a diverse group of aggressive B cell lymphomas, suggesting a potential new avenue for treating the most common type of non-Hodgkin lymphoma.

The investigators report in Cancer Cell that a group of drugs known as bromodomain inhibitors shut down the cancerous growth of diffuse large B cell lymphoma (DLBCL) cells grown in laboratory dishes, and also in animal models receiving implants of the cancer. One author called it a "very striking effect."

DLBCL is a heterogeneous group of lymphomas that develop in B cells of the immune system; they compose about 30 percent of non-Hodgkin lymphomas, which affect white blood cells and cause enlarged lymph nodes, fever, and weight loss. Standard treatment is chemotherapy and radiation, which cures about 60 percent of patients. Novel targeted drugs are being developed for treating relapsed and resistant disease in the remainder of patients.

There is much current interest in bromodomain proteins as drug targets in treating cancer. The proteins, which are not abnormal themselves, can stimulate over-activity of cancer-related genes.

Margaret Shipp, MDMargaret Shipp, MD

Because the bromodomain-inhibiting drugs showed encouraging activity against a broad array of DLBCL subtypes, further research is warranted, said the authors, led by James Bradner, MD, and Margaret Shipp, MD, chief of the Division of Hematologic Neoplasia at Dana-Farber.

"Our findings establish the rationale for using bromodomain inhibitors in lymphomas," said Bradner. His research team at Dana-Farber developed the inhibitor drug, JQ-1, one of the bromodomain inhibitor used in the DLBCL study. A version of JQ-1 has recently begun clinical trials in patients with advanced solid tumors.

Shipp said, "We have learned something important about the regulatory elements that control growth in these lymphomas and have identified bromodomain inhibition as a potentially attractive target across all these subtypes of DLBCL."

Although the drugs stymied the cancer cells' growth, it was not immediately clear how they worked. "We saw that JQ1 had a very striking effect across all the subtypes of lymphoma cell lines," said Shipp. "So we asked, what might be the explanation?"

Their experiments revealed that the bromodomains blocked activity of transcription factors, including E2F1, OCA-B, and MYC, that are implicated in cancerous growth. Transcription factors control the rate at which DNA blueprints are processed to make proteins. Therefore their inhibition results in an inability of the lymphoma cells to "reboot" their B-cell program after cell division and they stop growing.

Another way the bromodomain proteins are involved in DLBCL is by attaching themselves to "super-enhancer" sites on DNA molecules. Super-enhancers are recently identified control elements, like switches with variable settings, that boost activity of genes. The super-enhancers regulating the DLBCL genes proved to be highly susceptible to being disrupted by bromodomain inhibition, the experiments showed.

Bradner said that the lymphoma cells had become dependent on the bromodomain mechanism to fuel their growth, explaining why blocking bromodomain activity was so effective. The same methods used to identify the DLBCL cells' vulnerability to bromodomain inhibition "suggests a strategy for discovering unrecognized cancer dependencies" in other forms of cancer, Bradner said.

First authors of this study are Bjoern Chapuy, MD, PhD, and Michael McKeown, both of Dana-Farber.

Support for the research was provided by National Institutes of Health grants P01 CA92625, RO1 CA176745, and KO8 CA128972, along with grants from the Leukemia & Lymphoma Society #6446-13, the Damon-Runyon Cancer Research Foundation, and others.

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