A recent study finds that, TACE inhibitors currently developed for treating rheumatoid arthritis can also be employed to control proliferation of tumor cells. TACE is strongly present in a form of breast cancer, which responds poorly to current therapies.
TACE (tumor necrosis factor-alpha-converting enzyme) acts like a "molecular scissors" that releases a pair of ligands, called Amphiregulin and TGF-alpha, from the cell surface. These ligands activate EGFR.
EGFR, which stands for Epidermal Growth Factor Receptor, is the protein on the outer surface of a cell that is activated by EGF and related growth factors and signals for the cell to divide. Given that one of the hallmarks of cancer is cell division run amok, the reduction of high levels of EGFR activity has long been a primary target for anti-cancer drug development. So far, however, drugs aimed at directly inhibiting EGFR activity have met with only limited success in the cancer clinic, primarily in a small number of lung cancers.
Bissell and Kenny, researchers with the U.S. Department of Energy's Lawrence Berkeley National Laboratory (Berkeley Lab) have demonstrated that by targeting TACE (also known as ADAM17) with either molecular inhibitors or short interfering RNAs (siRNAs) that silence the TACE gene, the shedding of Amphiregulin and TGF-alpha ligands could effectively be blocked.
This also resulted in the inhibition of EGFR signaling and the reversion of malignant characteristics in tumor cells. It is the first reported use of protease inhibitors to stop breast cancer cell proliferation and restore the normal breast tissue structure.
Tumor cells, says Bissell, exist in the same microenvironment as healthy cells and must therefore appropriate normal physiological processes to facilitate their growth and spread. This idea can open up potential new avenues and targets for diagnostic and therapeutic applications.
"Because of this, we turned our attention to the processes that regulate the production of the ligands which bind and activate EGFR," Kenny said. "We reasoned that this binding and activation is essential for EGFR activation and that finding a way to block this interaction might prove to be an important additional approach to explore for inhibition of this pathway."
"We have designed an entirely new way of targeting EGFR signaling in breast cancer," said Kenny. "Almost all the work to date has involved the use of antibodies that stick to kinases or drugs that block kinase activities."
"Women with those types of tumors would seem to be poorly served by existing treatments and may stand to benefit from therapies that are based on the inhibition of TACE activity," said Kenny. "We would like to see some of the companies who have developed the new generation TACE inhibitors for treatment of rheumatoid arthritis also consider evaluating them in cancer patients."
"TACE inhibition has the potential to be an effective means of stopping tumor growth for EGFR-dependent cancers outside the breast as well," she added.