Targeted cancer therapies like PARP inhibitors succeed for some patients but fail others, posing a key oncology challenge. Researchers led by Dr. Louise Fets at the LMS map drug distribution in ovarian tumors using advanced imaging on patient samples. Findings show lysosomes—cellular recycling compartments—trap certain drugs, releasing them gradually and determining treatment outcomes.
Uneven Drug Spread in Tumors
PARP inhibitors have boosted ovarian cancer survival rates, yet resistance develops in many cases. Effective drugs must accumulate in cancer cells to trigger death, but distribution within tumors remains unclear. This analysis reveals variations not just in tumor access but in internal spread.
Live patient tumor slices, or explants, received PARP inhibitor treatment. Mass spectrometry imaging produced detailed maps of drug locations, paired with spatial transcriptomics to assess gene activity in high- and low-drug zones within identical samples. Drug concentrations fluctuated widely across tumor regions and patients, despite identical doses.
“Mass spectrometry imaging enabled direct visualization of drug uptake in patient tumors. Spatial mapping identified high- and low-drug areas, allowing gene expression comparisons from the same slice via spatial transcriptomics,” states Dr. Zoe Hall, senior author and Associate Professor at Imperial’s Department of Metabolism, Digestion and Reproduction.
Lysosomes Act as Drug Reservoirs
Lysosomes cause this unevenness by sequestering specific PARP inhibitors like rucaparib and niraparib. Drugs accumulate in these organelles, forming slow-release stores that extend exposure in affected cells while sparing others. Olaparib avoids this trapping.
“Single-cell drug levels varied greatly due to lysosomal buildup. These act as reservoirs, storing and releasing drugs to heighten cancer cell exposure,” explains Dr. Carmen Ramirez Moncayo, first author and Postdoctoral Researcher at the LMS.
Path to Personalized Therapies
PARP inhibitors treat ovarian, breast, and prostate cancers, with trials underway for others. Insights into lysosomal storage promise tailored strategies to boost efficacy and curb resistance.
“Cellular drug uptake explains variable responses. Analyzing tumor molecular signatures could enable personalized therapies,” notes Dr. Louise Fets, senior author and Head of the LMS’ Drug Transport and Tumour Metabolism Group.
In patients, disorganized tumor blood vessels may amplify uneven delivery. Upcoming work with animal models and expanded studies will probe these dynamics in relapsed cases.
