Researchers at City of Hope discovered that suppressing a specific protein activated in many types of cancer is critical to the effectiveness of a new kidney cancer drug. The team published its study in the March 15 issue of Cancer Research, the journal of the American Association for Cancer Research.
The findings suggest a new strategy to improve kidney cancer therapy, potentially boosting patients’ outcomes.
Until recently, kidney cancer patients, especially those with later-stage tumors, had few options for treatment. But the recent discovery of new drugs that specifically interfere with the mechanisms of cancer, such as the way tumor cells grow and nourish themselves, have expanded options for kidney cancer therapy. These drugs include temsirolimus and sunitinib.
|Robert Figlin strives to improve therapies for kidney cancer. (Photo by Thomas Brown)|
Sunitinib blocks growth factor receptors that encourage new blood vessels to nourish tumors and chemical signals that instruct tumors to continue growing. Clinical trials with sunitinib showed it works well on tissue samples, but does not perform as well or as consistently in patients themselves.
“While sunitinib has shown great efficacy in the laboratory setting, its results in clinical practice have not been as successful or uniform,” said Hua Yu, Ph.D., professor of cancer immunotherapeutics and tumor immunology and the study’s senior author. “We needed to better understand the drug’s mechanism of action on a cellular and molecular level to identify how we could potentially improve its effect in patients and to develop drugs to use in combination to improve its efficacy.”
Yu collaborated with Robert A. Figlin, M.D., Arthur and Rosalie Kaplan Professor of Medical Oncology and acting cancer center director, to study exactly how sunitinib works on kidney cancer cells.
Tumors survive and grow in part by suppressing and evading the immune system. City of Hope researchers found that sunitinib actually reduces kidney cancer cells’ immunosuppressive effects. The scientists showed that these antitumor properties may be due to the drug’s relationship to a protein called STAT3.
In a healthy person, the signal transducers and activator of transcription (STAT) family of proteins help manage cell growth and survival. In cancer patients, a form of STAT called STAT3 is highly active in cancer cells. That helps tumors grow and suppresses the body’s immune response around tumors. Cancer cells effectively become invisible and evade destruction.
In the study, the City of Hope team discovered that sunitinib causes kidney cancer cells in mice to shut down and commit a form of “cellular suicide,” a process known as apoptosis. They also found that levels of active STAT3 proteins correlated with how effectively sunitinib caused this apoptosis in cancer cells. The less STAT3, the better the drug worked.
Although sunitinib itself can inhibit STAT3, high levels of STAT3 from tumors can overcome that inhibition. Ultimately, according to the scientists, the high STAT3 levels can stunt sunitinib’s effectiveness against cancer.
Researchers tested this link by engineering certain genes in tumors to activate STAT3 in a way that could not be blocked by sunitinib. They found that those modified tumors showed greater resistance to sunitinib and were able to avoid apoptosis and continue growing.
Yu has published extensively on STAT3 activation and has validated STAT3 as a target for new drug development.
“New therapies like sunitinib and temsirolimus have rewritten how we treat renal cell carcinoma, and it’s important that we take advantage of these types of inroads in our fight against cancer to develop more targeted treatments,” said Figlin, who has conducted several clinical trials of investigational therapies for kidney cancer.
“With our greater understanding of sunitinib, we can work on combinatory therapies that may boost the efficacy of these treatments and help provide patients with better outcomes.”
More than 50,000 people were diagnosed with kidney cancer in 2008 and about 13,000 patients died from the disease, according to the American Cancer Society. The overall 5-year survival rate for all stages of kidney cancer is about 65 percent.