Researchers outlined molecular mechanisms in prostate cancer and shared potential opportunities for precision oncology.
In a recent review, lead author Giulia Ambrosini, PhD, and colleagues explored molecular mechanisms in prostate cancer to identify opportunities for precision oncology and therapeutic development. They emphasized the concept of “metabostemness,” which refers to the interplay between oncometabolites, epigenetic changes, and cancer stem cells.
“This phenomenon underscores the reciprocal interaction between cancer metabolism and stemness, where aberrant metabolites can reshape the epigenetic landscape to bolster stemness traits and promote a more malignant phenotype,” the authors explained.
The therapeutic implications outlined in the review focused on two areas: current strategies for detecting prostate cancer and opportunities for novel targeted therapies.
Biomarkers for Prostate Cancer Detection
Dr. Ambrosini and colleagues reviewed previously published data to share strategies for diagnosing prostate cancer through molecular identification. They listed several methods for detecting specific biomarkers in bodily fluids and biopsied tissue.
For instance, patients’ urine might be used to detect biomarkers. Researchers explained succinate is less abundant in the urine of patients with prostate cancer (n=32) versus healthy controls (n=32), which suggests a disruption of the tricarboxylic acid cycle in cancerous cells. Patients with prostate cancer also had lower levels of hydroxyglutarate and significantly higher median levels of kyneurine in their urine (n=101) when compared with controls (n=52).
Another option is patients’ seminal fluid. As prostate cancer develops, zinc and citrate levels decline as part of metabolic reprogramming. Multiple studies have shown patients with prostate cancer have lower levels of citrate in their seminal fluid compared to controls, Dr. Ambrosini and colleagues wrote.
Molecular profiling of cancer biopsies may also reveal new features of solid tumors. For example, fumarate, which is linked to the expression of the oncogenic HIF1ɑ and NF-kB pathways, has been shown to have higher concentrations in cancer samples than in benign tissue (n=13).
“Tessem et al., 2016, tried to shed light on the metabolic profiling of solid tumors and find biomarkers despite different and complex mixtures of tissues within the sample,” Dr. Ambrosini and colleagues said. “By selecting samples with a similar proportion of tumor and stroma across biopsies and groups, they could identify differentially elevated levels of succinate and reduced levels of citrate between [patients with prostate cancer] (n=95) and healthy individuals (n=34).”
Lactate has also been linked with in situ tumor progression. Although its concentration is generally low, researchers have used transrectal ultrasound-guided biopsies to detect higher lactate levels in cancer samples when compared with benign tissue (n=82).
“Interestingly, they could reach an ability to detect this increase in lactate with as little as 5% of tumor content in the biopsy, making it a promising tool for [prostate cancer] detection,” Dr. Ambrosini and coauthors wrote.
In addition, the use of extracellular vesicles (EVs) has expanded recently, authors noted. In a study published in 2018, researchers conducted a metabolic analysis of isolated EVs and found succinate in all samples (prostate cancer n=31; benign prostatic hyperplasia n=14), with a fold-change of 1.211 (P=0.11).
“Furthermore, succinate has been identified in EVs derived from PC cells in vitro, with significantly higher levels than non-tumoral counterparts,” the authors said.
Researchers also have identified significantly lower levels of citrate and isocitrate in the EVs of patients with prostate cancer, while high concentrations of lactate and fumarate have appeared in patient-derived cancer-associated fibroblasts.
Opportunities for Therapeutic Development
Dr. Ambrosini and colleagues went on to identify opportunities for developing targeted therapies—particularly agents that could halt cancer progression by modifying the tumor microenvironment.
Mutations in metabolic enzymes such as succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase give rise to oncometabolites linked to changes in DNA and histones. Dr. Ambrosini and coauthors speculated small molecule inhibitors or other agents targeting these mutated enzymes could stop the production of oncometabolites and, subsequently, cancer progression.
Dr. Ambrosini and colleagues said therapies might also be designed to target specific markers associated with cancer stem cells and epithelial-to-mesenchymal transitions. These therapies could provide a means of eliminating cancer stem cells, halting metastasis, and reversing therapy resistance.
“The future of prostate cancer research involves a multidimensional approach, focusing on risk stratification, personalizing treatments, and continually developing novel therapies,” the authors wrote. “The key lies in exploiting these intricate relationships to identify potential therapeutic targets and develop effective treatment strategies for not only prostate cancer but also other types of cancer where similar mechanisms are involved.”
