The discovery of the HER2 gene in breast cancer led to a targeted therapy, Herceptin, that has dramatically boosted survival in women whose tumors are HER2-positive, an aggressive type of breast cancer that was previously hard to treat. Now scientists at University of Michigan Comprehensive Cancer Center (UMCCC) in Ann Arbor have announced what may be an equivalent discovery for prostate cancer, a gene called SPINK1 that could be a potential treatment target for an aggressive form of the disease.
The HER2 and SPINK1 genes have striking similarities, says Scott Tomlins, MD, Ph.D., co-author of the study, published March 2 in Science Translational Medicine, and a pathology resident at UMCCC. “Each defines a specific molecular subtype of cancer.” About 20 percent of breast cancer tumors have multiple copies of the HER2 gene, while the SPINK1 gene occurs in about 10 percent of prostate cancer tumors.
What’s more, adds Tomlins, “both genes are highly expressed on the surface of cancer cells, so they could be targeted through monoclonal antibodies,” the drug category that includes Herceptin. Monoclonal antibodies act like smart bombs, attacking specific targets on cancer cells, while sparing normal cells.
To see if this treatment approach could be effective for SPINK1-positive tumors, the scientists compared the effects of two targeted therapies, using mice and cells from human prostate cancers that had been surgically removed from patients. First, the researchers tested an experimental monoclonal antibody designed specifically to block SPINK1. Since the gene binds to a cellular receptor called EGFR (epidermal growth factor receptor) in cells, the scientists also studied a medication that blocks EGFR, cetuximab (Erbitux), a FDA-approved drug for colon cancer and head and neck cancer. Tumors treated with the SPINK1 antibody shrank 60 percent, while those treated with Erbitux dwindled by 40 percent. Combining both drugs cut tumor size in mice and human cancer cells by 74 percent.
Scientists develop genetic-based treatment for prostate cancer.
However, the drugs only worked on tumors that expressed SPINK1—a finding that may explain why a clinical trial using Erbitux to combat metastatic prostate cancer in human patients was a failure, with only 8 percent of participants showing any response, says Tomlins. “That wasn’t enough of an effect to make further clinical trials with this drug seem worthwhile, but our data suggest that the patients who responded may have been those who were SPINK1-positive,” since only 10 percent of tumors contain the gene. Given that 217,730 men will be diagnosed with prostate cancer this year, more than 21,000 of them may fall into this category, putting them at risk for aggressive disease.
Since prostate cancer may behave differently in mice—or in human cells studied in the lab—clinical trials with men whose tumors express SPINK1 are the only way to find out if Erbitux is effective at extending the survival of such patients. If that turns out to be the case, points out Tomlins, cancer doctors could quickly start using the drug as a new weapon against aggressive disease. “The drug is already FDA-approved for other cancers, meaning that its side effects and safety have already been rigorously investigated in clinical trials.” The other drug tested in the UMCCC study, the SPINK1-blocking antibody—is designed for mice, so would require considerable modification and additional tests before it can be studied in humans.
Over a lifetime, one in six men will develop prostate cancer. In most cases, the disease progresses very slowly and may never become life-threatening. However, prostate cancer is expected to kill 32,050 American men this year. It’s crucial for doctors to better identify which men have aggressive disease, both to improve treatment for those who do, and to potentially spare those with non-aggressive disease unnecessary treatment that could put them at risk for such feared side effects as incontinence and impotence. Since the SPINK1 gene can be detected in urine, the discovery of the gene might lead to a simple, non-invasive screening test in the future. In a previous study involving about 1,500 men with prostate cancer, the researchers found that the gene can be reliably identified in surgically removed tumors, offering another method that might be used in the future to evaluate how aggressive prostate cancer is—and what treatment is most likely to be effective.
The current study represents a breakthrough in understanding aggressive prostate cancer, believes Tomlins. “What’s most important is that prostate cancer, like breast cancer, isn’t a single disease with a one-size-fits all treatment that works for everybody who has it. Finding gene changes that drive specific cancer subtypes, so treatment can be tailored to the right targets is a very hot field in cancer research, and prostate cancer has lagged behind. We hope that our results push forward more investigation into targeted therapies that may bring men with the SPINK1 subtype more benefit.”
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