Tumor Resistance to Breast Cancer Therapy
Reported January 07, 2010
(Ivanhoe Newswire) — Researchers have found a clever way to override signals that tell breast cancer cells to thrive in the face of anticancer treatment. The investigational agent renewed the vulnerability of resistant breast cancer cells to treatment by fulvestrant.
The researchers, from Georgetown University Medical Center (GUMC) Lombardi Cancer Center, added that this method would likely work equally well with tamoxifen, the world’s most commonly used breast cancer drug. Both fulvestrant and tamoxifen are used in women with estrogen-receptor-positive metastatic breast cancer. Both drugs have a history of falling prey to eventual tumor resistance. Fulvestrant is typically used when women stop responding to tamoxifen.
The Lombardi researchers reported that the agent, YC137, a broadly active drug that inhibits multiple members of the Bcl2 family of proteins, restored the ability of breast cancer cells to self-destruct in several different ways. Previously, it was believed that the Bcl2 protein family was involved in only apoptosis, one method of cell death that programs self destruction, lead investigator Robert Clarke, PhD, DSc, professor of oncology and physiology & biophysics at GUMC was quoted as saying.
“There are other ways that a cell dies, and our research shows that Bcl2 is involved in these processes as well. That means it is possible to hit a number of these Bcl2 pathways that breast cancer cells use to evade the killing effects of a drug,” said Clarke. “We need to block all of the alternative routes cancer uses to survive.”
In this study, laboratory experiments using YC137 restored the ability of fulvestrant to bind to and destroy estrogen receptors in several different lines of tumor cells. The findings explain why treatments that target just one member of the Bcl2 family have not done as well, and it suggests that using an agent that can hit multiple Bcl2 proteins will be more effective, according to Clarke.
That could mean a Bcl2 blocking drug could be administered along with other traditional cancer therapies to keep the tumor cells from becoming resistant due to activation of a Bcl2 survival mechanism. Several Bcl2 blocking drugs are now in clinical trials, Clarke added.
“We are using a systems biology approach that looks at all genes and proteins involved in breast cancer to identify what else is playing a role in keeping these cells alive,” he said. “We want to know what all the targets are that we need to hit to make sure these cells are destroyed, and these might provide other exciting opportunities for drug discovery.”
SOURCE: PLoS ONE, January 6, 2010