SAN ANTONIO (August 1, 2013) – Researchers at the UT Health Science Center have been awarded a $1 million grant from the Susan G. Komen Foundation to help them zero in on a new way to treat triple-negative breast cancers.
Currently there are no known targets in triple-negative breast cancers where highly specific drugs could be developed to hit only the tumors and not healthy cells.
Pothana Saikumar, Ph.D., an associate professor of pathology in the School of Medicine at The University of Texas Health Science Center at San Antonio, believes his team, including postdoctoral fellow Prajjal Singha, Ph.D., has identified one therapeutic target and a possible biomarker that would benefit a large group of patients with this disease.
Understanding the mechanisms of these cells will give researchers a roadmap for developing targeted therapies that do not have the harsh side effects of many current chemotherapies.
The idea: for any cancer to develop it must escape the body’s surveillance mechanisms — the immune system and a protein called TGF-beta. Both play very conflicting roles. They have the ability to eliminate cancer cells but also to promote cancer cell growth.
TGF-beta is a strong inhibitor of cell proliferation, so it acts as a tumor suppressor at the beginning of tumor development. However, during cancer progression cancer cells become resistant to TGF-beta. In fact, it supports tumor growth and metastasis and promotes immune evasion and angiogenesis — the formation of new blood vessels that can feed tumor growth.
In patients with triple-negative breast cancer, TGF-beta expression is generally high and allows the cancer to avoid the body’s immune defenses.
“Until now we have not known when TGF-beta reaches that tipping point” from cancer suppressor to cancer promoter, Dr. Saikumar said, “but we believe our research has identified this tipping point in the form of TMEPAI gene expression.”
The TMEPAI protein is amplified in triple negative breast cancer. Its expression becomes further elevated in the presence of TGF-beta. Thus, cancer cells multiply normally or even abnormally at higher levels in presence of TGF-beta. However, normal cells, which produce no or very little TMEPAI, stop multiplying in the presence of TGF-beta.
Even more interesting is what keeps normal cells in from expressing TMEPAI. The researchers identified other growth signals that act to block TMEPAI expression in normal cells. If these growth signals are blocked, then normal cells begin to multiply much like cancer cells even in the presence of TGF-beta.
“Our research points to TMEPAI as the switch that turns TGF-beta from a tumor suppressor to a tumor promoter,” Dr. Saikumar said. “Now we are addressing the question: what is the mechanism by which this protein allows cancer cells to avoid immune surveillance?” This work will be carried out in collaboration with Tyler Curiel, M.D., MPH, a professor in the School of Medicine at the Health Science Center and cancer immunologist.
Currently, in order to block the proliferation of cancer cells, researchers have been focusing on the development of broad-spectrum TGF-beta inhibitors. However, these drugs may cause problems with the TGF-beta’s normal role in cardiovascular system maintenance and tumor suppression – encouraging the growth of other tumors as well as affecting cardiovascular health.
By defining the growth-suppressive and growth-promoting roles of TGF-beta, we can develop drugs that will only target oncogenic activity while preserving the positive functions TGF-beta has in the body.
Using mouse models, we identified novel compounds that inhibited TMEPAI, promoted TGF-beta activity and inhibited cancer cell proliferation. These compounds may have the potential of not only inhibiting tumor growth but also preventing tumor recurrence and occurrence.
Click here for more information on the grant, and here for more information on the Susan G. Komen Foundation.
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.