New Class of Breast Cancer Drugs Offers New Hope
November 29, 2011 – Georgetown cancer researchers continue to make strides toward developing a new class of drugs that could revolutionize the prevention and treatment of the most common types of breast cancer.
Most breast cancers are fueled by estrogen. Oncologists typically treat these "estrogen-receptor-positive" (ER+) cancers with tamoxifen and other drugs that either interfere with the estrogen receptor or prevent the body from producing estrogen.
But ER+ tumors can develop resistance to these treatments.
The new compounds that oncology professor Eliot Rosen and his team are developing would work on tumors that have developed this resistance.
"We are hopeful that our compounds can be developed into drugs that will be useful both for breast cancer prevention and for treatment, particularly for anti-estrogen-resistant cancers, either by themselves or in combination with conventional anti-estrogens," says Rosen, who holds the Gragnani Chair in Oncology and Radiation Biology at Lombardi Comprehensive Cancer Center.
The research offers new hope for patients for whom anti-estrogen treatments have stopped working – or haven't worked at all.
At higher doses, these compounds could be used to block the growth of breast cancers that have developed resistance to tamoxifen. At lower doses, they could be used with tamoxifen to enhance its effectiveness or to render it effective in cancers that have stopped responding to the drug.
Rosen and his team are focusing on BRCA1 – a powerful tumor suppressor gene that helps repair damaged DNA or signals a cell's destruction if it can't be repaired.
In the 1990s, Rosen and his colleagues discovered that the tumor suppressor protein from BRCA1 binds to and inhibits the estrogen receptor (ER), a breakthrough that was published in Science magazine. This binding activity stops the growth of ER-positive breast cancer cells.
Rosen found BRCA1 also blocks the cells from responding to estrogen. When the gene is mutated or missing, a woman's risk of developing breast cancer increases to more than 50 percent.
"Tumor suppressors often have more than one function," Rosen says. "We think that both the DNA repair function and the estrogen receptor inhibition functions of BRCA1 contribute to its ability to suppress breast cancer formation."
He and his team have been studying how BRCA1 physically interacts with the estrogen receptor.
After identifying where this interaction occurs, the team developed a 3D computer model of the BRCA1-ER complex. Rosen and his team can now "see" exactly where these proteins bind to each other, and how the binding domains are structured.
On the Road
The molecular compounds that Rosen and his team are currently developing bind to the estrogen receptor in the same way BRCA1 does.
Rosen now plans to test the safety and efficacy of two of these compounds in pre-clinical studies, which are required before an agent can be approved for testing in people.
"I think we are well on the road toward that goal," Rosen says.