A team of NIH-funded scientists has developed a new method that changes the way genes are regulated to effectively cause cancer tumors to shrink and die in the laboratory. Supported in part by a Penn State University Clinical and Translational Science Institute (CTSI) pilot grant award and research funding from the National Cancer Institute (NCI), Penn State professors Yanming Wang and Gong Chen recently published work in the Journal of Biological Chemistry suggesting that stopping the action of an enzyme called PAD4 (peptidylarginine deiminase 4) sets off a chain reaction of "molecular switches" in cancer cells. The effect is to switch the internal cell signals from growth to death.
Funded in part by NIH’s Clinical and Translational Science Awards (CTSA) program, this multidisciplinary team, is hopeful that their discovery will aid in the development of anti-cancer drugs that only target cancerous tissue without damaging healthy cells and vital organs. Chemotherapy, a standard cancer treatment, damages both healthy and diseased cells. The studied anti-cancer drug has the potential to reduce or eliminate these side effects and improve chemotherapies for cancer patients.
PAD4 alters proteins called histones that package and regulate DNA in a process called "epigenetics," which alters gene function without changing the DNA sequence. This process is often involved in activating and deactivating genes ― turning genes on and off. Interestingly, PAD4 has been found in concentrations greater than usual in numerous types of human cancers, such as breast and bone cancer. This PAD4 "overexpression" also appears to be involved in such autoimmune diseases as rheumatoid arthritis and multiple sclerosis. Wang and Chen are using cell cultures and mouse tumor models to explore the way excess PAD4 affects cells.
With funds from NCI, the Wang group previously found that PAD4 blocks tumor suppressors, which stop tumor growth. This led them to suspect that they could block cancer growth by turning off PAD4. A PAD4 inhibitor was already known, but it could not easily get through the cell membrane, so Chen, a chemist, created several new compounds that could block PAD4 activity.
Wang, who is a biochemist and molecular biologist, found that a low dose of one of these compounds, called YW3-56, killed tumor cells in culture and in a tumor mouse model, shrinking tumors by up to 50 percent. Cancer cells responded very quickly to the treatment, suggesting that the compound easily penetrated the cells. Wang and Chen found that YW3-56 can work in combination with a compound called SAHA (suberoylanilide hydroxamic acid), another gene inhibitor that acts epigenetically, to increase tumor death to up to 70 percent. This rate is similar to what the traditional chemotherapy drug doxorubicin achieves.
Further, the dose needed to kill cancer cells does not harm normal, healthy cells, unlike traditional chemotherapy. "Because the PAD4 treatment appears to be less toxic, it could be an excellent alternative to current chemotherapy treatments," Wang said, "making it a promising agent for a variety of cancers and diseases that over-express PAD4."
The researchers found that when the PAD4 inhibitor turns on tumor suppressor genes, the cell-programming systems that encourage cell growth turn off. In fact, blocking PAD4 encourages a process in which the cells recycle their own components. In the tumor cell lines and mouse tumor model tested, the cells began to completely dismantle themselves and die. As Chen and Wang continue to conduct experiments to generate enough information to perform human clinical trials, pharmaceutical companies are already expressing interest in their work. The researchers currently are focusing their efforts on using YW3-56 and other inhibitors in breast cancer, but these inhibitors have the potential to be used in a variety of cancer types and autoimmune disorders.
"Without pilot funds from our CTSI, this collaborative research would not have gotten off the ground," Chen said.
Posted July 2012