City of Hope scientists are testing a three-in-one therapy to fight cancer, targeting the critical protein known as STAT3.
Hua Yu, Ph.D., professor in the Department of Cancer Immunotherapeutics and Tumor Immunology, explains that STAT3 helps cancers develop and grow in numerous ways. But since STAT3 is a factor inside the nucleus of the cells, she said, it is difficult to inhibit using currently available approaches. Now she and her colleagues have created a technology platform to silence STAT3 and other key immunosuppressive genes that cannot be blocked with today’s drugs.
|Marcin Kortylewski searches for ways to block STAT3. (Photo ©2007 Philip Channing)|
The researchers published their findings in the October issue of Nature Biotechnology. Marcin Kortylewski, Ph.D., is lead author on the paper.
The story begins with the human immune system and its relationship to cancer. Normally, the immune system fights off infections and cleans up cellular damage. When a cancerous tumor develops, though, the tumor instigates a cascade of signals that turn off the immune response around it and protect it from immune cells. Yu’s group wants to wake up immune cells to overcome the immune-suppressing environment around a tumor.
The STAT3 protein helps tumors to evade the immune response. It also plays a part in cancer’s growth. Turning STAT3 expression off disables angiogenesis — the tumor’s ability to build new blood vessels to feed itself — which effectively starves it. Targeting STAT3, then, may hold promise as a treatment strategy.
Yu’s group has been exploring RNA interference as a way to quiet STAT3 in cancer and stimulate cancer-fighting immune cells. “In order to target immune cells specifically, we looked at using the ligand for TLR9 receptor for siRNA targeted delivery,” said Yu.
Because Toll-like receptor 9 (TLR9) is a protein receptor that identifies bacterial and viral infections and signals the immune system to destroy them, it may also serve as an “on button” for immune cells.
Yu and her team developed a strategy links short-interfering RNA (siRNA) targeted at STAT3 expression to a small piece of DNA, a ligand that seeks out the TLR9 receptor inside certain immune cells. “In linking siRNA together with a TLR9 ligand, we created a single synthetic molecule capable of working against cancer on three levels,” said Yu. “The therapy is targeting immune cells, silencing STAT3 expression to turn off immunosuppression, and provoking an immune response against the cancer cells through TLR9 activation.”
In the lab, the research team compared anti-tumor activity using the STAT3 siRNA alone to the new conjugate version of the STAT3 siRNA with the TLR9-seeking molecule.
“We found that the conjugate therapy elicited more active antitumor activity than the STAT3 siRNA alone,” said Yu. “There are several factors that may be involved and we need further study to better understand the mechanisms at work.”
Yu’s team is continuing the development of the conjugate with safety trials, as well as research into improving the structural stability and antitumor action of the therapy. The researchers believe the conjugate may become a platform for new therapies that pair other disease-specific siRNA with TLRs to address cancers and autoimmune diseases.
City of Hope collaborators include Piotr Swiderski, Ph.D., John J. Rossi, Lidow Family Research Chair in the Department of Molecular Biology, Stephen J. Forman, M.D., Francis and Kathleen McNamara Distinguished Chair in Hematology and Hematopoietic Cell Transplantation, and Richard Jove, Ph.D., director of Beckman Research Institute. Jove made the first connection between STAT3 and cancer. Drew Pardoll, M.D., Ph.D., of Johns Hopkins University also contributed to the work.