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A closer look at splicing
BUFFALO, N.Y.—Two researchers from the Roswell Park Comprehensive Cancer Center have identified biomarkers for aggressive prostate cancer and opened the door to personalized treatment. The six-year study, recently reported in Nature Communications, could lead to treatment that targets abnormal RNA splicing prevalent in advanced tumors, as well as the ability to identify more aggressive prostate cancers from those that progress more slowly.
Dean Tang, chair of Pharmacology and Therapeutics at Roswell Park and senior author of the study, and Song Liu, vice chair of Roswell Park’s Department of Biostatistics and Bioinformatics, led the study launched with the intention to learn how prostate cancer cells differ from normal, healthy prostate cells. In particular, the work explored how those cancerous cells transcribe their genes. Researchers focused on alternative splicing, the process by which a DNA sequence is transcribed into RNA forms in an abnormal manner compared to healthy cells, which then results as tumors.
“Cancer cells are obviously bad cells, but they may also have abnormal—what we would call ‘deregulated’—molecular and biological properties that may make them vulnerable,” Tang says. “We wanted to explore whether those vulnerabilities could be identified and exploited.”
Aggressive prostate tumors “are those that, at the time of diagnosis, have high pathological grade (e.g., Gleason Grade 9 or 10) and/or already have metastasis,” Tang explains. “Most aggressive tumors will not be eligible for surgery, unlike the ‘regular’ or low-grade tumors. Another class of aggressive prostate tumors would include those that have been treated but become treatment-refractory, e.g., castration-resistant. Generally, prostate cancer patients with aggressive, metastatic and treatment-refractory tumors would die within two to three years.”
According to Tang, more aggressive tumors “could potentially be treated differently,” noting that: “Now, for example, most high-grade (advanced) prostate tumors are treated with androgen-deprivation therapy or ADT. But if the prostate cancer patient with a high-grade tumor also has metastases outside of the prostate, i.e., being more aggressive, this patient can be treated with a combination of ADT and chemotherapy such as docetaxel. The combination treatment can also be ADT plus radiation or immunotherapy.”
“Aggressive prostate tumors are identified by pathological analysis of the patients’ tumor biopsies, as well as by the clinical manifestations,” Tang remarks. “In our studies, aggressive prostate tumors are characterized by their unique gene expression profiles.”
Liu expands on that, adding that “In normal and benign prostate epithelial cells, introns are generally spliced out or ‘thrown away’, meaning that they will not be transcribed into mRNA and will not be turned into peptides or small proteins. In contrast, in high-grade, aggressive prostate tumor cells, many introns are not spliced out and instead get transcribed into RNAs.”
Tang and Liu are planning the next direction for this research.
“We are already asking whether retained introns may be translated into short snippets of proteins called peptides that can be used for tumor vaccine development,” Liu reports. “And we are generating preliminary data for NIH grant applications. The published six-year study was supported by a combination of grants and private funding.”
The team found that as prostate cancer progresses and becomes more aggressive, gene splicing also becomes more unregulated, meaning the RNA splicing pattern is increasingly abnormal. In addition, very aggressive cancer cells are more likely to splice RNA in abnormal fashion, and those aggressive prostate cancer types are more frequently enriched by retaining introns, segments of genetic code that do not become proteins. These observations are consistent with emerging data in other cancer types, Liu says.
“We found, surprisingly, that when prostate cancer cells become more aggressive, they have more genes that retain the introns in their messenger RNA, or mRNA,” Liu tells DDN. “We have observed this retention and also noted that retention of introns is more pronounced in advanced tumors.”
Currently, clinicians do not have reliable methods for determining whether a prostate tumor is indolent (does not require immediate treatment) or dangerously aggressive, the researchers state. But the abnormal alternative RNA splicing patterns in aggressive prostate cancer could potentially be developed into biomarkers that could be used to distinguish between the two types of tumors. Roswell Park Cancer Center’s findings also reveal that aggressive prostate cancers might be more susceptible than indolent tumors to chemical inhibitors of the splicing machinery.
Tang and Liu “are also investigating how many of the retained introns in aggressive prostate tumors may be able to become peptides for vaccine development,” Tang comments. “Eventually, we hope we could exploit the retained introns to develop immunotherapeutics to specifically target the aggressive prostate cancer.”