UC Davis researchers find new clues to workings of promising prostate cancer drug
Study suggests PSA and survivorship not enough to evaluate drug effectiveness
UC Davis Cancer Center researchers have shed light on how a promising prostate cancer drug works, revealing additional potential drug targets. The researchers, who are also among those conducting clinical trials of the drug, say the findings are an important step in the search for treatment options for what is now an incurable form of prostate cancer, called castration-resistant prostate cancer. The study appears online now and published in the journal Oncogene.
"This new pill is part of our efforts to develop targeted therapies for prostate cancer," said Christopher Evans, senior author of the study and chair of the UC Davis Department of Urology. "We believe this drug has great potential to extend the lives of patients with incurable prostate cancer."
The drug — currently referred to as AZD0530 — has little toxicity and works by inhibiting communication between cancer cells and their growth.
Although prostate cancer is the second-leading cause of cancer death in men in the United States, there are few treatment options. It is estimated that there will be about 186,320 new cases of prostate cancer in the United States in 2008 and about 28,660 men will die of the disease this year. Thanks to improved screening efforts, many cases are diagnosed early. Currently, treatment options include chemotherapy and surgery to remove the prostate and, in more advanced cases, the testes.
—Christopher Evans, study senior author
The growth of prostate tumors is controlled by the male hormone testosterone, a type of androgen. To reduce this growth, either the testes are removed or drugs are given to block the production of testosterone. Over 90 percent of prostate cancers respond to surgical or chemical castration. However, all patients who initially respond to this treatment will eventually develop castration-resistant prostate cancer, which is highly invasive and likely to spread to other organs.
UC Davis Cancer Center Clinical Trials
A cancer clinical trial is designed to answer a specific question. For example: Is a promising investigational drug effective? Does a newly approved drug work even better with an older drug? Which is more effective, chemotherapy followed by surgery, or surgery followed by chemotherapy?
Cancer clinical trials are carried out in phases:
- Phase I trials evaluate how a new drug should be given, how often and at what dose. A Phase I trial usually enrolls a small number of patients.
- Phase II trials test how effective a new drug or procedure is against a particular cancer.
- Phase III trials compare a promising new drug, new combination of drugs or new procedure with the best standard treatment. Phase III trials typically involve large numbers of patients, usually hundreds or thousands. A patient in a Phase III trial is randomly assigned to receive either the new treatment or the best existing treatment.
- Phase IV trials ask new questions about standard treatments. A Phase IV trial might test how a newly approved drug works together with other effective drugs, or with surgery and/or radiation therapy.
The drug Evans and his colleagues studied works by blocking a signaling protein called Src (pronounced "sarck") that specializes in messages that control the growth and spread of cells. The DNA that encodes the Src protein is known as an oncogene, because the gene is intimately connected with the development of cancer. In the current study, researchers conducted experiments using both cell cultures and animal models.
Yu-Ming Chang, the study's lead author and a UC Davis M.D./Ph.D. candidate at the time the work was conducted, said he and his colleagues implanted prostate cancer cells into mice and then treated them with the drug.
"We were able to identify some of the molecular pathways the drug blocks. We showed that the drug inhibits tumor growth by about 45 percent in our animal model," he said. "These results give us the mechanistic rationale to keep pursuing this drug as a potential treatment in patients."
According to Evans, the study also revealed other potential drug targets involved in the Src pathway and molecular markers that would indicate the drug is working.
Currently, the effectiveness of prostate cancer treatments is determined by decreases in prostate-specific antigen (PSA) levels and patient survivorship. In early trials of AZD0530, PSA levels were not significantly reduced.
"When we go back to the lab and look at whether PSA is a good marker for this drug, we find that it is not," Evans explained. "Despite little change in the PSA levels in mice, tumor growth was significantly slowed. Our study supports the case for redesigning the clinical trials testing this drug using different molecular markers to evaluate success."
Evans added that continued laboratory studies on the effects of blocking Src will be crucial to evaluating ongoing clinical trials of AZD0530, which is also being tested in the treatment of leukemia, melanoma, and breast and colon cancers.
"The work in the lab is critical to the work in the clinic, and vice versa. This bidirectional science helps us understand the pathways that are involved, find new targets and identify new translational endpoints," he said.
In addition to Evans and Chang, UC Davis study authors were Hsing-Jien Kung, professor, Department of Biological Chemistry; Lanfang Bai, assistant specialist, and Joy Yang, assistant researcher, Department of Urology; and Shangqin Liu, postdoctoral fellow, Department of Biological Chemistry and Molecular Medicine. The study was supported by grants from the National Institutes of Health and the U.S. Department of Defense.
Designated by the National Cancer Institute, UC Davis Cancer Center is leading the way in identifying the molecular pathogenesis of carcinoma of the prostate, enhancing therapeutic response and identifying chemopreventions. For more information, visit the cancer center Web site.