Drug Combination Prevents ER-Negative Tumors in Mice

BOSTON—Two experimental drugs used together were shown to be far more effective than either alone in preventing the development of estrogen-receptor-negative (ER-) breast tumors in mice, Karen Liby, PhD, a postdoctoral fellow at Dartmouth Medical School, said at the AACR's Frontiers in Cancer Prevention Research meeting (abstract PR-08). One of the drugs, LG100268, developed by Ligand Pharmaceuticals, Inc., San Diego, California, is a rexinoid, which binds to retinoid X receptors. Known as 268, the agent has previously been reported to be effective in preventing and treating mammary tumors in animal models of ER+ breast cancer.

The other agent, CDDO-ME, developed at Dartmouth, is a synthetic triterpenoid, a type of compound found in plants throughout the world. CDDO-ME had already been shown to inhibit proliferation and induce apoptosis in ER+ and ER- breast cancer cell lines as well as block the growth of ER- breast cancer cells in immunodeficient mice. CDDO-ME is currently being tested in clinical trials of leukemia and solid tumors.

These two drugs were tested in a mouse mammary tumor virus (MMTV)-neu mouse model of ER- breast cancer. In this transgenic model, mice develop breast tumors because of the targeted expression of the neu gene, also known as erbB2 or HER2, in the mammary gland. "We start feeding the mice 268, CDDO-ME, or the combination once the mammary glands are fully developed at 10 weeks of age," Dr. Liby said.

While the 15 control mice had 100% tumor incidence at roughly 40 weeks of age, the incidence was only 12% in the mice on CDDO-ME and 29% in the mice on LG100268 (8 mice in each treatment group). "Most significantly, no tumors were found in the group fed a combination of both drugs," she said. After an additional 3 months, 50% of the mice on CDDO-ME and 43% on 268 had developed tumors, but still no tumors were found in the combination group. The drug concentrations used in this experiment were well tolerated, and the mice continued to gain weight during the trial.

"We significantly delayed time to tumor development. This drug combination appears to be highly effective for chemoprevention and should be considered for future prevention trials," she said.

The researchers are about halfway through repeating their experiment with the mice, and they plan to move into a treatment protocol in which they will allow tumors to form and then treat the mice with 268 and CDDO-ME alone and then in combination.

In previous work using the same mouse model for ER- tumors, Dr. Liby and her colleagues found that the combination of 268 and either of two investigational SERMs (selective estrogen-receptor modulators), arzoxifene and acolbifene, synergistically prevented tumor development for up to 1 year. These drug combinations also were effective as treatment agents.

The Dartmouth group is also hoping to collaborate with researchers involved with another ER- mouse model, the BRAC1 knock-out model. Dr. Liby said they are interested in testing 268, the triterpenoids, and SERMs in this model.

Michael Sporn, MD, principal investigator for this work at Dartmouth, said that "ultimately for chemoprevention, we will have a very safe cocktail of multiple agents that can be given to people at very low doses. To prevent cancer, we need a variety of drugs acting in a variety of ways and acting synergistically."