Spatial modulation enhances the effects of radiation on prostate cancer cells: a targeted mass spectrometry metabolomics study.

Abstract

Purpose: Spatially modulated radiation fields, such as microbeam or grid therapy, have been shown to enhance tumor cell killing while sparing normal tissue compared to uniform fields of the same total dose. The biological mechanisms underlying this effect remain poorly understood. This study investigates metabolomic changes in prostate cancer and normal prostate cells following exposure to spatially modulated versus uniform irradiation.

Materials and methods: Prostate cancer (LNCaP) and normal prostate (PNT1A) cells were irradiated using spatially modulated or uniform fields at equivalent, higher, or lower mean doses. Metabolites from cellular extracts were profiled using targeted liquid chromatography-mass spectrometry (LC-MS) selected reaction monitoring (SRM). Multivariate analyses, including principal component analysis (PCA) with bootstrapping, were applied to identify dose- and field-dependent metabolic signatures.

Results: PCA revealed a clear dose-response in uniformly irradiated LNCaP cells and distinct separation between non-irradiated and irradiated groups. Notably, cancer cells exposed to modulated fields clustered closer to those treated with a higher-dose uniform field than to those receiving the same mean dose, suggesting biological equivalence to dose escalation. Key metabolites driving this separation were associated with phenylalanine, tyrosine, and tryptophan biosynthesis pathways, indicating heightened metabolic stress under modulated irradiation. In contrast, PNT1A cells showed no significant metabolic distinction between modulated and uniform fields of the same mean dose.

Conclusion: Spatially modulated irradiation induces metabolic responses in prostate cancer cells comparable to those elicited by higher-dose uniform fields, while normal cells respond similarly to uniform fields of the same dose. These findings provide mechanistic insight into the therapeutic advantage of spatial modulation and support its potential role in improving tumor control without increasing normal tissue toxicity. Given that clinical radiotherapy sessions typically span 15-30 minutes, incorporating spatial modulation and temporal fractionation strategies into treatment workflows may offer a practical and effective means to improve therapeutic outcomes in prostate cancer.