The findings, presented at the American Association for Cancer Research in San Francisco, shed light on the molecular mechanisms involved in developing resistance to a drug that targets the epidermal growth factor receptor (EGFR) – a key growth signaling pathway in cancer. Further, the laboratory findings show that using a different targeted drug after resistance occurred, effectively inhibited tumor growth, suggesting that prostate cancer can be effectively kept at bay with various therapies used sequentially over time. This is similar to how advanced breast cancer is treated today.
“Understanding the mechanisms involved in the growth and treatment of prostate cancer will ultimately enable us to offer our patients other targeted therapies when they stop responding to a given drug,” said David Agus, M.D., Research Director at the Cedars-Sinai Prostate Cancer Center and senior author of the study.
The drug, called ZD1839, or Iressa, developed by AstraZeneca, has been found to work in both laboratory and clinical trials by targeting and turning off a key growth-signaling pathway called the epidermal growth factor receptor (EGFR). Otherwise known as HER1, the EGFR is a part of the HER kinase family of proteins that regulate cell growth and can stimulate the spread of tumors when over-expressed on cancer cells.
In the laboratory study, the researchers evaluated the effectiveness of ZD1839 in two types of human prostate cancer tumors grown in mice: Those with tumors that were either dependent on testosterone to grow (androgen-dependent); or the type that grew independently of testosterone (androgen-independent). (Tumors that grew independently of testosterone are characterized by prostate cancer that has developed resistance to standard treatment with drugs that block the production of testosterone.) The drug was then given to the two groups of mice orally (with a dropper) five times a week for three weeks and compared to a control group of mice that received no drug. The investigators found that tumor growth was inhibited by 53 percent in the androgen-dependent group and by 47 percent in the androgen-independent group, as compared to the controls in which no tumor regression occurred.
“These results tell us that ZD1839 effectively inhibited tumor growth in both types of prostate cancer, which may ultimately mean that we can offer patients a targeted therapy that works without the side effects caused by hormone therapy,” said Dr. Agus.
To determine whether the mice would eventually develop resistance to ZD1839, the researchers re-implanted tumors that had shrunk in response to the drug into a new host group of mice and resumed treatment with ZD1839. They found that the mice developed resistant tumors after multiple rounds of treatment with ZD1839.
After the mice stopped responding to treatment with ZD1839, the investigators wanted to determine whether different targeted drugs would combat resistance. First, they gave the mice who had developed resistant tumors a drug called OSI774 (Tarceva), developed by Genentech and OSI Pharmaceuticals that works by a similar mechanism to ZD1839, but found that the tumors continued to grow. Second, the investigators gave the same mice an experimental drug called rhuMAb 2C4 – a monoclonal antibody developed by Genentech that blocks cell signaling from the HER kinase family of proteins. They found that rhuMAb 2C4 inhibited tumor growth by 60 percent.
“These findings indicate that attacking cancer with drugs that target the appropriate molecular pathway during the treatment process may offer patients the best and most successful treatment outcomes,” said Dr. Agus.
Cedars-Sinai Medical Center is one of the largest non-profit academic medical centers in the Western United States. For the fifth straight two-year period, Cedars-Sinai has been named Southern California’s gold standard in health care in an independent survey. Cedars-Sinai is internationally renowned for its diagnostic and treatment capabilities and its broad spectrum of programs and services, as well as breakthrough in biomedical research and superlative medical education. Named one of the 100 “Most Wired” hospitals in health care in 2001, the Medical Center ranks among the top 10 non-university hospitals in the nation for its research activities.