New Target Identified for Preventing Castration-Resistant Prostate Cancer

A new study published in Nature Communications is suggesting that castration-resistant prostate cancer (CRPC) has particular metabolic characteristics that may open new possibilities for treatment.

Researchers combined patient-derived prostate cancer gene expression with metabolomic data and identified a vital role for hexosamine biosynthetic pathway (HBP) in the castration-resistant state.

The investigators have found that  downregulation of HBP enhances tumorigenicity of CRPC-like cells via activation of cell cycle genes regulated by either the PI3K-AKT or the SP1-ChREBP axis. They report that treatment with UDP-N-acetylglucosamine (UDP-GlcNAc) may significantly decrease proliferation and tumor growth of CRPC-like cells while increasing efficacy of the antiandrogen enzalutamide (Xtandi) in vitro.

“Using an innovative approach to integrate gene expression and metabolomics data, we identified key metabolic pathways that are altered in prostate cancer,” said study author Arun Sreekumar, PhD, professor of Molecular and Cellular Biology at Baylor College of Medicine, Houston, in a news release. “Of these metabolic pathways, the hexosamine biosynthetic pathway showed significant alterations.”

The researchers discovered that HBP is much less active in castrate-resistant than in androgen-dependent prostate cancers. In addition, reduced HBP activity is likely to enhance tumor growth.

Sreekumar explained that when the researchers experimentally knocked down genes involved in HBP in cells similar to CRPC tumor cells, the cells responded with a marked increase in proliferation, both in cell culture and animal experiments. When the cells with reduced HBP received UDP-N-acetylglucosamine, a product of this metabolic pathway they lacked, the cells slowed down their growth.

These results indicate that studying the metabolic characteristics of tumors resistant to therapy offers the possibility of discovering new targets to treat cancer. HBP may be that potential therapeutic target for CRPC, a disease that accounts for close to 30,000 deaths annually in the United States.

For this current experiment, the researchers used metabolomic and transcriptomic profiles from a previous study containing 12 treatment-naive localized prostate cancer specimens and 16 benign adjacent prostate tissues. They integrated these profiles using a novel pathway-centric analytical framework, which combines two rankings for each pathway calculated from gene expression and metabolic data. 

Sreekumar and his colleagues report that the precise molecular alterations driving CRPC are not clearly understood. However, the researchers hoped that by using a novel network-based integrative approach, that enables researchers to collect high-throughput genomic, proteomic, and metabolomic data, it may be possible to overcome resistance to androgen deprivation therapy (ADT).