SAN ANTONIO (October 8, 2014) — Tyler Curiel, M.D., M.P.H., an oncologist and immunologist at the Cancer Therapy & Research Center, was trying to solve a mystery in ovarian cancer when the search led him to a mirror-image puzzle in lupus: the roles played by estrogen and the immune system.
“What’s cool is that insight in one area led to a discovery in another area, and both can benefit,” said Dr. Curiel, who also holds the Daisy M. Skinner Chair in Cancer Immunology Research in the
School of Medicine at The University of Texas Health Science Center at San Antonio.
That groundwork has led to a $1.12 million federal grant to figure out the precise set of hormone signals that allow estrogen to interfere with the body’s healthy immune function, and could lead to an important breakthrough in lupus treatment. The grant is through the Congressionally Directed Medical Research Program of the Department of Defense.
And now the team is at the point where lupus patients can help with a simple blood donation. That sample will help the researchers get a clearer idea of the process of immune function.
“Your immune system has a really complicated job. It’s got to figure out what’s supposed to be there and what’s not,” Dr. Curiel said. “It’s the Homeland Security of your body.”
And sometimes a tool the immune system uses to protect against one kind of disease actually works to enable the development of another.
Dr. Curiel and his team had focused in on a specific molecule called B7-H1 that is a “bad actor” in ovarian cancer. They found that female mice that were missing this molecule were protected against ovarian cancer because the body was able to reject the cancer cells.
“That suggested that the B7-H1 molecule made it difficult to recognize what’s not supposed to be there and get rid of it,” he said.
If the researchers took the mice who were missing the B7-H1 molecule and removed their ability to produce estrogen by taking out their ovaries, the mice lost their cancer protection. When they gave those same mice estrogen again, the mice were again able to defend against cancer. So there was some kind of relationship between the B7-H1 molecule and estrogen.
But what? Understanding this meant understanding B7-H1’s complex job in the body.
As one of its functions, B7-H1 controls a type of immune cell that defends against autoimmune disease called a regulatory T cell, or Treg.
That was key for Curiel and his team.
Tregs stop the body from having autoimmune disease, but too many and they can prevent anti-cancer immunity.
Estrogen can keep Tregs from functioning. One of the roles of B7-H1 is blocking estrogen from interfering with Tregs, in essence defending Tregs from estrogen. So what makes the B7-H1 molecule a bad actor in ovarian cancer can make it a good actor in the case of autoimmune disease.
“I wasn’t thinking about autoimmune disease when I began,” Curiel said. “If you have cancer all these Tregs are bad for you. If you have lupus all these Tregs are good for you. It’s a balancing act.”
To get a better look at this dynamic, Curiel and his team looked for a clear example of an autoimmune disease where estrogen makes it worse.
The answer is lupus.
Dr. Curiel’s initial work led to a $300,000 grant from the Lupus Research Institute in 2011, along with support from the Holly Beach Public Library Association. That allowed them to dig into the details of why lupus primarily affects women.
The research in turn supported groundwork that led to the federal grant, which will help them get to the “how” of it: the precise mechanism of hormone signaling. For that, Dr. Curiel is partnering with some of the CTRC’s experts in that area: Ratna Vadlamudi, Ph.D., professor of obstetrics and gynecology, who is co-investigator on the grant, and Rong Li, Ph.D., professor of molecular medicine.
“We need to better understand how B7-H1 protects Tregs from estrogen – then we might be able to use that information to treat autoimmune diseases,” Dr. Curiel said.
If the researchers can define that function, they can develop new classes of drugs that are highly effective and specific, and Dr. Curiel and his collaborators expect to identify the pathway in the next three years.
“With new technology we can move much more quickly than we used to in drug development,” he said. “But also, once we understand the pathways of cell signaling, we have a pretty good record of identifying a drug that’s already out there and approved for another use.”
People with lupus or other autoimmune disease who are interested in participating in the research can call Rosie Hatley at 210-450-1438.
The Cancer Therapy & Research Center (CTRC) at The University of Texas Health Science Center at San Antonio is one of the elite academic cancer centers in the country to be named a National Cancer Institute (NCI) Designated Cancer Center, and is one of only four in Texas. A leader in developing new drugs to treat cancer, the CTRC Institute for Drug Development (IDD) conducts one of the largest oncology Phase I clinical drug programs in the world, and participates in development of cancer drugs approved by the U.S. Food & Drug Administration. For more information, visit www.ctrc.net.