Testing for genetic weaknesses in repairing DNA could help identify men who may benefit from a new type of targeted nuclear medicine, suggests a study* published today in the journal European Urology.
An emerging class of drugs are made up of a radioactive particle that can kill cells attached to a “homing device” to seek out cancers by detecting the presence of a target molecule on their surface.
These new “search-and-destroy” treatments are starting to show promise even in men with prostate cancer for whom targeted treatments and chemotherapies have stopped working, but not all patients respond.
In the new study, scientists at The Institute of Cancer Research, London, found that testing men for faults in DNA repair genes in their tumours could identify those most likely to respond to the new type of treatment.
The study was funded by the Movember Foundation, Prostate Cancer UK, Cancer Research UK and the Prostate Cancer Foundation.
The researchers analysed tumour samples from 38 men with advanced prostate cancer who had been treated at The Royal Marsden NHS Foundation Trust, in order to understand why the response to “search-and-destroy” treatment varied.
They found that the target for these new treatments – a protein molecule called prostate-specific membrane antigen (PSMA) – was present at higher levels on the surface of cancer cells in some patients than others. PSMA levels even varied substantially between different cancer sites in the same patient.
Crucially, the amount of PSMA on the surface of cancer cells was more than four times higher in tumours where there were also faults in DNA repair genes.
That means that testing for genetic faults in DNA repair genes could be used as a first-stage screen to select patients for PSMA-targeted treatment, followed by having tumours scanned using PSMA imaging technology.
The researchers believe that PSMA plays a key role in keeping the genome in cells stable and could be produced by tumours as a survival mechanism where they are defective in repairing their DNA.
These findings also suggest that combination therapy with other drugs that increase genetic instability could make prostate tumours more likely to respond to PSMA-targeting treatments.
The researchers said they now planned to assess whether testing for DNA repair faults could effectively target search-and-destroy treatment as part of clinical trials, and to explore combination strategies to see if the response to these treatments could be heightened.
Precise targeting of cancer cells and use of drug combinations are among a range of strategies being pursued at The Institute of Cancer Research, London, through its new Centre for Cancer Drug Discovery.
Professor Johann de Bono, regius professor of cancer research at the Institute and consultant medical oncologist at The Royal Marsden NHS Foundation Trust, said: “Our new study helps to explain why some patients respond to search-and-destroy treatments and others don’t. Understanding the biology of response to these new treatments is critical to getting them into use in the clinic as soon as possible.
“We will need to further assess the use of DNA tests to target these treatments effectively in routine care, but we can already now start to take into account DNA repair faults in our design of clinical trials.”
*Paschalis A, et al. Prostate-specific Membrane Antigen Heterogeneity and DNA Repair Defects in Prostate Cancer. Eur Urol (2019). DOI:10.1016/j.eururo.2019.06.030.