A study published in Nature Communications by a team led by Dr Louise Fets at the LMS reports on Mar. 17 that the way certain cancer drugs are stored inside cells could influence how well treatments work for ovarian cancer patients. The research focused on PARP inhibitors, a group of targeted therapies, and used advanced imaging techniques to map their distribution in patient tumour samples.
The findings matter because while PARP inhibitors have improved outcomes for many ovarian cancer patients, some do not respond or develop resistance over time. Understanding why these differences occur could help improve treatment strategies and patient prognosis.
Researchers treated thin slices of human ovarian tumours with PARP inhibitors and observed how the drugs spread within the tissue. Using mass spectrometry imaging, they created detailed maps showing where drug molecules accumulated. They also used spatial transcriptomics to compare gene activity in regions with different drug levels within the same sample. The results showed significant variation in drug concentration across different areas of a single tumour and between patients, even when given the same dose.
Dr Zoe Hall, senior author and Associate Professor at Imperial's Department of Metabolism, Digestion and Reproduction, said: "A novel aspect of this study was the use of mass spectrometry imaging to directly measure and visualise drug uptake in patient tumour tissue. 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."
The team found that lysosomes—cell compartments that act as recycling centers—were trapping some PARP inhibitors like rucaparib and niraparib but not others such as olaparib. This storage created internal reservoirs that slowly released drugs over time, exposing some cells more than others.
Dr Carmen Ramirez Moncayo, first author and Postdoctoral Researcher at the LMS, said: "We were surprised to see large variability in drug accumulation at the single-cell level. This variability was driven by the build-up of a drug in lysosomes, which are acting as reservoirs, increasing the exposure of cancer cells to drugs, by storing and releasing the drug when needed."
PARP inhibitors are already widely used for ovarian, breast, and prostate cancers. Dr Louise Fets said: "By understanding how drugs are taken up into cells, we can understand whether this influences why cancer drugs work for some people and not for others. Eventually, we hope to be able study the molecular signature of a patient's tumour to help to tailor therapeutic approaches in a more personalised way."
The researchers note that their study used tumour tissue maintained outside the body; real-world factors like blood vessel structure may further affect drug delivery in patients. Future studies will use animal models and larger patient groups to better understand these mechanisms.
