A multimodal imaging study has revealed marked heterogeneity in the distribution of poly(ADP-ribose) polymerase (PARP) inhibitors across ovarian tumors, with some regions showing far higher drug accumulation than others. The findings suggest that lysosomes can act as reservoirs for certain PARP inhibitors, creating hotspots of high exposure alongside regions with much lower drug levels.
PARP inhibitors have transformed treatment options for high-grade serous ovarian carcinoma, but resistance remains a major clinical problem, and the impact of tumor heterogeneity on intratumoral drug distribution and efficacy is still poorly understood. To address this, researchers developed a multimodal pipeline using thin slices of patient tumor tissue cultured ex vivo to examine drug uptake independently of the vasculature.
The workflow combined matrix-assisted laser desorption/ionization mass spectrometry imaging with spatial transcriptomics and immunohistochemistry across adjacent tissue sections. Explants from treatment-naive ovarian tumors were dosed with olaparib, niraparib, or rucaparib, then cryosectioned for parallel analysis. Mass spectrometry imaging revealed marked heterogeneity in drug accumulation between patients, between tumor sites from the same patient, and within individual tumor slices.
“A novel aspect of this study was the use of mass spectrometry imaging to directly measure and visualize drug uptake in patient tumor tissue,” said senior author Zoe Hall in the team’s press release. “Through the spatial mapping of drug molecules, we could pinpoint regions of high and low drug and compare gene expression, from the same tissue slice, using spatial transcriptomics.”
High-drug regions were enriched for apoptotic and DNA damage response signatures, while the strongest shared transcriptomic signal in niraparib- and rucaparib-rich regions was lysosomal. In follow-up cell experiments, rucaparib colocalized with lysosomes within 30 minutes, and altering lysosomal pH or content changed intracellular levels of rucaparib and niraparib, but not olaparib. This suggests that weak-base PARP inhibitors can accumulate in lysosomes, whereas olaparib does not.
The study suggests that lysosomes do not simply trap these drugs, but can act as slow-release reservoirs that sustain nuclear drug levels and increase DNA damage. “We were surprised to see large variability in drug accumulation at the single-cell level,” said first author Carmen Ramirez Moncayo. “This variability was driven by the build-up of a drug in lysosomes, which are acting as reservoirs.”
The authors say larger patient cohorts and in vivo studies will be needed to clarify how tumor architecture, vascular delivery, and lysosomal storage shape clinical resistance. “Eventually, we hope to be able to study the molecular signature of a patient’s tumor to help tailor therapeutic approaches in a more personalized way,” said Louise Fets.
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