Mutant Protein May Change Treatment Plans for Prostate Cancer

Rebecca J. Boohaker, Ph.D., and colleagues are researching a mutated protein that may define a distinct subclass of prostate cancer.

Prostate cancer is the most common non-skin cancer in American men and remains a significant health risk. Scientists at Southern Research in Birmingham are studying a mutated protein that could hold the key to both development and treatment of this disease and possibly make the cancer more susceptible to radiation treatment.

Rebecca Boohaker, Assistant Fellow in Southern Research's Drug Discovery Oncology Department, and postgraduate researcher Joshua Fried are focusing on the Speckle-Type POZ Protein (SPOP) which is mutated in up to 20 percent of primary prostate tumors and can define a distinct subclass of prostate cancer and possibly determine the aggressiveness and progression of the disease.

"There are five relevant mutations that appear in the patient population, but we are focusing on the SPOP because it is involved in DNA damage repair mechanisms," Fried says. "If you look at the three-dimensional representation of proteins, most mutations occur in the same domain of the protein that is responsible for targeting other proteins for degradation. As a result, mutations render the SPOP ineffective in a way that contributes to the disease progression, because the turnover of normal proteins is altered."

Data has revealed that the presence of mutant SPOP causes an enrichment of genes that previously had been associated with mutant BRCA1, a gene that is mutated in some breast and ovarian cancers. The identity of the affected genes suggests that SPOP not only affects DNA repair pathways but also blocks a process called homology-directed repair, a method that cells normally use to repair double-stranded DNA breaks.

Boohaker says they recently isolated a specific mutation, Serine 119 to Asparagine. "We have been trying for a while to characterize this specific mutation that prevents a protein from being phosphorylated by an upstream protein that is responsible for DNA damage repair," she says. "We want to use this as a biomarker which says that if you do have a mutation in this protein at this specific location, it will make your prostate cancer more susceptible to radiation treatment."

The presence of the SPOP mutation could change a patient's treatment plan based on the aggressiveness of the cancer. It would be specific to each patient and include radiation treatment or some kind of DNA damaging chemotherapy.

"We want to spare patients from treatments that may not be as effective and streamline them into those you know will work best," Fried says. "Chemotherapy and radiation can be tough, so we want to spare patients from seemingly unnecessary treatments."

Boohaker isn't sure how many people are using these recent findings which are available in multiple databases, but she is sure that the findings have important implications for prostate cancer treatment. "I think the S119 mutation is present in about 10 percent of the population, but when you consider the number of men diagnosed with prostate cancer each year in the United States and around the world, the numbers add up quickly," she says. "

Next steps in their research are to leverage the new proteins that have been dysregulated by the mutated SPOP and explore the options those proteins might provide. "We have to validate which targets are the most appropriate to pursue in our discovery efforts," she says. "Then we will try to implement some of these findings into a clinical setting where they can be considered by physicians who are diagnosing and developing treatment plans for prostate cancer patients."


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Speckle-Type POZ Protein (SPOP); prostate cancer mutations; serine 119 to aspara


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