Blood mRNA Model Predicts Castration Resistance in Prostate Cancer
Peripheral blood mRNA sequencing can be used to develop prognostic models for progression to metastatic castration-resistant prostate cancer, researchers reported following the publication of findings in Front Oncol. on October 14, 2026. The prognostic model identifies specific transcriptomic signatures linked to treatment resistance, offering a potential tool for risk stratification before clinical failure becomes apparent.
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Key Clinical Takeaways:
- Researchers built a three-gene prognostic model from peripheral blood mRNA to predict metastatic castration-resistant prostate cancer.
- The study analyzed a prospective cohort of 157 enrolled patients treated at Sichuan Cancer Hospital and Institute.
- Elevated expression of the candidate gene SLC6A8 correlated with shorter progression-free survival in external genomic datasets.
Single-Cell Transcriptomics and Gene Selection at Sichuan Cancer Hospital
Investigators initiated the study by examining single-cell transcriptomic data from the GSE288878 dataset to isolate genes associated with metastatic castration-resistant prostate cancer. They paired these findings with transcriptome sequencing performed on peripheral blood samples gathered from a prospective cohort at Sichuan Cancer Hospital and Institute in Chengdu, China. Between February 1, 2024, and February 1, 2025, researchers screened 230 patients, ultimately enrolling 157 participants who met eligibility criteria. These patients were randomly divided in a 7-to-3 ratio into development and validation cohorts, with 147 individuals successfully completing the required follow-up period.
Eligible participants presented with de novo metastatic hormone-sensitive prostate cancer, demonstrated at least one measurable lesion according to RECIST 1.1 guidelines, and maintained an ECOG performance status of 2 or lower. Treatment regimens across the cohort consisted of androgen deprivation therapy combined with an androgen receptor pathway inhibitor, with or without docetaxel. Disease progression was adjudicated using Prostate Cancer Clinical Trials Working Group 3 criteria. At a median follow-up of 611 days—spanning a 95% confidence interval of 560 to 641 days—54 patients progressed to metastatic castration-resistant prostate cancer.
Intersecting differentially expressed genes from the patient cohort with single-cell data revealed five candidate genes: SLC25A39, GRB10, SELENBP1, SLC6A8, and YBX3. Subsequent elastic net-regularized Cox regression narrowed these selections down to a final three-gene signature. Researchers noted that this transcriptomic framework aims to address clinical ambiguity in patients with equivocal risks, such as those presenting with oligometastatic bone disease or borderline prostate-specific antigen levels.
Evaluating SLC6A8 as a Glycolysis-Promoting Biomarker
Further analysis of The Cancer Genome Atlas prostate cancer dataset, comprising 498 patients, established that elevated expression of SLC6A8 in tumor tissue serves as an independent risk factor for shorter progression-free survival. To investigate underlying mechanisms, researchers tested the SLC6A8 inhibitor ompenaclid in C4-2B castration-resistant prostate cancer cells. The pharmacological agent suppressed cellular proliferation and promoted apoptosis in a dose-dependent manner. Treatment with ompenaclid downregulated glycolysis-associated genes including HK2, PFKP, and ALDH1B1, while lowering glycolytic metabolites such as lactic acid, pyruvic acid, and fructose-1,6-bisphosphate.
Despite these mechanistic insights, the study authors acknowledged several methodological limitations. The investigation relied on a single-center design limited to an exclusively East Asian population, lacked an external validation dataset, and featured a small validation cohort with a limited number of events that yielded wide confidence intervals. The current follow-up duration supports projections of only one to 1.5 years, and mechanistic findings depended on pharmacologic inhibition in a single cell line.
To address these constraints, investigators are planning a prospective multicenter validation study across three to five tertiary centers in China. While the transcriptomic signature could eventually help clinicians select candidates for treatment intensification or guide the omission of specific agents like docetaxel in favorable molecular phenotypes, the study authors emphasized that these applications remain hypothetical pending prospective validation.
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