Drug combinations may improve triple negative breast cancer treatment
Researchers led by Baylor College of Medicine have found a new way to tackle a difficult-to-treat form of breast cancer – a discovery that is being translated into human studies with currently approved FDA drugs.
The new strategy begins with their discovery that a gene called PTPN12 plays a pivotal role in triple negative breast cancer, an aggressive form of the disease that accounts for approximately 20 percent of new cases of the disease and is resistant to common drugs such as Tamoxifen and Herceptin®. Until now, the genes that drive the growth of triple negative breast cancer have been a mystery, making it difficult for scientists to devise new therapies for this disease.
In a report in a recent issue of the journal Cell, Dr. Thomas F. Westbrook of BCM and colleagues describe their new understanding of the forces that drive this aggressive disease and, more important, how to use a combination of drugs to block those forces.
PTPN12 prevents breast cancer
"This study gives us promising new insight into how to treat patients with triple negative breast cancer and possibly other cancers," said Westbrook, assistant professor of biochemistry and molecular biology and molecular and human genetics at BCM and senior author of the report.
In this study, Westbrook and his collaborator, Dr. Stephen J. Elledge of Harvard Medical School, screened literally tens of thousands of genes for their role in human breast cancer. They found that the gene PTPN12 prevents or suppresses breast cancer. Next, together with researchers at the BCM Lester & Sue Smith Breast Center, Westbrook showed that most triple negative breast cancers have lost that protective gene.
Most important, the researchers found that the loss of PTPN12 unleashes a specific combination of cancer-promoting enzymes called tyrosine kinases. These enzymes work in concert to cause aggressive growth and spread of triple negative breast cancer. Blocking just one kinase is not enough, said Westbrook. Specific combinations of kinases have to be blocked to stop the growth of the breast cancer.
Combining kinase inhibitors
Because drugs that block some of these kinases are already FDA-approved for patients, this study provides an exciting strategy for combining specific kinase inhibitors to combat triple negative breast cancer as well as other forms of cancer.
This double-barreled discovery gives researchers a new foothold from which to fight triple negative breast cancer.
"This discovery is an important advance for patients, because we may now be able to rationally combine drugs that inhibit these kinases to treat patients with triple negative breast cancer (and other cancers) that were previously thought intractable to such therapies," said Westbrook, also a member of the NCI-designated Dan L. Duncan Cancer Center.
Combos block spread
Westbrook and colleagues showed that inhibiting specific combinations of these kinases effectively blocks the growth and spread of triple negative breast cancer in animals. Because drugs that block some of these kinases are already approved for patients, this study provides an exciting strategy for combining specific kinase inhibitors to combat triple negative breast cancer as well as other forms of cancer.
Many researchers and physicians believe it will be important to combine drugs for cancer treatment," said Westbrook.
"But the strategy of which medicines to combine is difficult to predict. Here, we are providing a new rationale to combine a specific set of medicines to treat this debilitating disease, and we are now pursuing clinical trials to test this new idea."
May play role in other cancers
In addition to triple negative breast cancer, PTPN12 may play a role in other difficult-to-treat malignancies such as lung cancer. In fact, there may be a whole class of genes that behave like PTPN12 to inhibit kinases and cancer formation.
"By discovering these new genes and how they work, we think we can develop new therapies for many types of cancer," said Westbrook.
Others who took part in this study include Tingting Sun, Kristen L. Meerbrey, Jessica D. Kessler, Maria Botero, Jian Huang, Ronald J. Bernardi, Earlene Schmitt, Mitchell Rao, Chad J. Creighton, Susan G. Hilsenbeck, Chad A. Shaw, Donna Muzny, Richard A. Gibbs, David A.Wheeler, C. Kent Osborne, Rachel Schiff and Ilenia Migliaccio,, all of BCM; Nicola Aceto and Mohamed Bentires-Alj of the Friedrich Miescher Institute for Biomedical Research in Basel, Switzerland; Natalya Pavlova, Guang Hu, Mamie Li, Noah Dephoure, Steven Gygi, and Chunshui Zhou, all of Harvard Medical School, and Don Nguyen of Yale University School of Medicine.
Funding for this work came from The V Foundation and the Mary Kay Ash Foundation for Cancer Research, the Susan G. Komen for the Cure Foundation, the Special Program of Research Excellence of the National Cancer Institute, the U.S. Army and the Howard Hughes Medical Institute.