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Bromodomain Inhibition: Helping Cancer Cells “Forget”

April 2014 | eNews

The TPETT program, with its mission to facilitate the development of new anticancer agents from the preclinical to the clinical stages, relies on basic research to provide new compounds for study. An example of such basic research has taken place in the laboratory of James Bradner, MD (DFCI) and has led to the development of a first-in-class experimental anticancer agent, the bromodomain inhibitor, TEN-010.

According to Bradner, through a strategic initiative launched a few years ago, more scientists interested and trained in drug discovery were recruited to DFCI to expand its capabilities beyond testing cancer drugs in model systems. “Some cancers are too rare and some target cancer genes are too challenging to attract pharmaceutical efforts in drug discovery,” says Bradner. So, when Bradner joined DFCI five years ago, he sought to build a lab interested in the discovery and clinical translation of “creative” new types of cancer drugs.

To date, three agents have moved from Bradner’s lab into human clinical trials. In addition to TEN-010, a bromodomain inhibitor, two other agents—both histone deacetylase inhibitors—have entered into clinical trials: SHP-141, which is being studied in cutaneous T-cell lymphoma and ACY-1215, which is being studied in multiple myeloma.

The development of the bromodomain inhibitor TEN-010 started about four years ago when Bradner and a synthetic chemist in his lab, Jun Qi, PhD, reported in Nature the first inhibitor of a bromodomain-containing protein called BRD4. Bromodomain-containing proteins such as BRD4 increase the expression of genes that promote cancer cell proliferation and survival; therefore, targeting these proteins can be a potential therapeutic strategy against cancer. As Bradner describes it, bromodomain inhibitors “help cancer cells to ‘forget’ that they are cancer.”

The bromodomain inhibitor developed in his lab, initially called JQ1, was found to bind competitively to bromodomains within BRD4. Working with Christopher French, MD (BWH) they found that JQ1 induces squamous differentiation and growth arrest in BRD4-dependent NUT midline carcinoma cells. “We showed that JQ1 could turn the cells into a form of human skin that could be peeled off the bottom of a culture dish—it was very dramatic,” Bradner says. JQ1 also showed a striking benefit in mice with lung cancers; the tumors “literally melted away.”

Going against the standard drug-development approach, which is often shrouded in secrecy, Bradner and his colleagues employed an “open-source” approach about the next phase of development. They wanted to learn as much as possible about JQ1, and so they synthesized hundreds of grams of JQ1 and made it available worldwide for scientists to use in their research.

“Over the last three years, we have provided JQ1 to more than 400 laboratories free of charge and without restriction on its research use,” Bradner says, and “from this self-assembling network of scientific collaborators, several very exciting new opportunities for clinical use of bromodomain inhibitors have arisen.” According to Bradner, bromodomain inhibition holds great promise in blood cancers, such as lymphoma, leukemia, and multiple myelomas, as well as in pediatric cancers such as neuroblastoma and medulloblastoma.

After developing JQ1, the next step was to create a derivative of JQ1 that would be feasible to evaluate in humans, namely one that was potent, stable, and available in the form of a soluble derivative for clinical application. That effort led to the development of JQ2, and with that molecule, Bradner and Dana-Farber partnered with a startup pharmaceutical company, Tensha Therapeutics, to deliver the drug (now called TEN-010), back to academia for human clinical trials.

TEN-010 is now being studied in phase I clinical trials within the TPETT program at DFCI and at collaborating institutions. Over the next year, Bradner says he expects critical information will be learned that will help guide the further development of the compound.

The initial phase I clinical trial is evaluating TEN-010 in patients with solid tumors. A separate study is also underway for patients specifically with a BRD4 rearrangement. In addition, studies to evaluate this agent in hematologic cancers and in childhood tumors will open shortly.

“We are very excited, albeit anxious, to realize the promise of bromodomain inhibition in cancer,” says Bradner. “As a laboratory interested in the basic science of gene regulation and molecular pharmacology, it has been exhilarating to have a chance to so actively contribute to new cancer drug discovery.”

— Emma Nichols