A New Class of Breast Cancer Drugs

Eliot Rosen, MD, PhD, is well on his way to creating a new class of targeted therapy for the most common kind of breast cancer — a treatment that will hopefully work for tumors that have developed resistance to tamoxifen and other conventional anti-estrogens.

Eliot Rosen

Rosen, who holds the Gragnani Chair in Oncology and Radiation Biology at Georgetown Lombardi Comprehensive Cancer Center, has discovered a class of small molecules that he says can block the growth of breast cancers that have lost their sensitivity to tamoxifen and, in some cases, can restore the sensitivity of these cancers to tamoxifen when used in combination with tamoxifen.

This would be a major advance in the medical care of about two-thirds of breast cancer — the kind that is driven by estrogen and so is known as estrogen receptor-positive — because tamoxifen, which binds on to the estrogen receptor to block the hormone, often loses its effectiveness, resulting in regrowth of the cancer. And some patients with estrogen receptor-positive cancers do not respond to tamoxifen and other conventional anti-estrogens at all.

Given the potential of this new class of agents, Rosen has been supported by the National Cancer Institute and has received other grants, such as a recent $600,000 award from Susan G. Komen for the Cure.

“This is very exciting. We are not at the stage of conducting clinical trials, but I think we are well on the road toward that goal,” Rosen says.

That path became set in the 1990s when Rosen and his colleagues discovered that BRCA1 binds to and inhibits the estrogen receptor (ER), a breakthrough that was published in Science magazine.

BRCA1 is known as a powerful caretaker gene that helps repair damaged DNA or signals a cell’s destruction if repair is not possible. Rosen found it also blocks the cells from responding to estrogen, which is known to fuel breast cancer. 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 researchers in his laboratory then discovered another intriguing fact: If BRCA1 is mutated and prevented from functioning in breast cancer cells, those cells have an abnormal and completely opposite response to tamoxifen. “Tamoxifen, in those cases, actually stimulates the growth of these cells, rather than inhibiting it.

“So that tells us that BRCA1 modifies a cell’s response to tamoxifen -- when BRCA1 is missing, tamoxifen acts like a cancer stimulant,” Rosen says.

These findings suggested a reason why tamoxifen stops working — BRCA1 protein levels (produced by the gene) may sink too low to be effective — and it also offered a potential solution: a drug that mimics BRCA1’s action on the estrogen receptor.

To find such a drug, Rosen, Yongxian Ma, PhD, and York Tomita, PhD, studied in detail how BRCA1 physically interacts with the estrogen receptor. Having identified the exact regions of BRCA1 and the estrogen receptor that interact with each other, they used this information to develop a three-dimensional (3D) computer model of the BRCA1-ER complex. This allows scientists to “see” exactly where these proteins bind to each other, and how the binding domain is structured.

What they found is that BRCA1 binds to the estrogen receptor in a different area than does tamoxifen, whose job is also to inhibit activation of the receptor by blocking the ability of estrogen to activate the estrogen receptor.

Tomita then used the models of the binding interaction to compare it to the structure of small molecule drug-like compounds, trying to find one that would bind deeply to the same ER pocket that the BRCA1 protein does. The researchers screened 40 of the most promising compounds in cultured breast cancer cells and found six that strongly inhibited the activity of the estrogen receptor at low concentrations — just as BRCA1 does.

These molecules prevented the estrogen receptor activity as well as cell growth in ER+ breast cancer cells that were resistant to tamoxifen. Two of those molecules offered lovely extra benefits, Rosen says. In the process of binding to the estrogen receptor, they actually forced it to change its structure in a way that tamoxifen could bind and inhibit the estrogen receptor’s activity, even in cancer cells that were previously resistant to tamoxifen. Rosen says: “These are the first small molecule compounds that appear to overcome tamoxifen resistance and restore sensitivity.”

The researchers believe that these prototype agents could be developed into drugs that could be used in two different ways. At higher doses, they could be used to block the growth of breast cancers that have developed resistance to tamoxifen. At lower doses, they could be used in combination with tamoxifen to enhance its effectiveness or to render it effective in cancers that had stopped responding to tamoxifen.

He also points out that these molecules may also help other breast cancer drugs that bind to the same cavity on ER as tamoxifen. Tamoxifen is a SERM (selective estrogen regulator modulator), as is raloxifene and several other drugs, but another class of drugs, the SERDs (selective estrogen down regulators), such as fulvestrant, also targets the same area on the receptor.

“Our compounds bind to a completely different site, so this is potentially a new fourth class of targeted anti-estrogen breast cancer drugs,” Rosen says. (The 3rd class of drugs, aromatase inhibitors, works in a completely different way; they stop the production of the estrogen hormone in the tissues that make it.)

He now plans to test the safety and efficacy of the two compounds in pre-clinical studies — the types of studies needed before an agent can be approved for testing in humans.

“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,” Rosen says.

By Renee Twombly, GUMC Communications
(Published August 03, 2011)