Cancers such as prostate cancer can develop and progress because tumour-suppressor genes have either been lost or have mutated, but restoring these suppressors has proved difficult. A team of researchers from Brigham and Women’s Hospital (BWH), Boston Children’s Hospital and Memorial Sloan Kettering Cancer Center has now succeeded in reintroducing “PTEN” messenger RNA (mRNA) into prostate cancer cells by encapsulating it in nanoparticles. The innovative technique effectively restores tumour suppression in vivo, even when the cancer is in the metastatic stage, and might lead to the development of a new type of precision medicine for treating cancer.
PTEN (phosphatase and tensin homologue deleted on chromosome 10) is a tumour-suppressor gene that is lost or mutated in about half of all metastatic castration-resistant prostate cancers and in many other human cancers, explains co-team leader Jinjun Shi of BWH. Restoring functional PTEN as a way to treat prostate cancer has proved to be no easy task though. We have now shown that we can reintroduce functional copies of PTEN mRNA into PTEN-depleted prostate cancer cells both in vitro and in vivo by encapsulating it in polymer-lipid hybrid nanoparticles coated with a polyethylene glycol shell. This mRNA, which can be thought of as a tiny delivery vehicle that can get messages of genetic information into cells, restores the function of the PTEN tumour suppressor gene. It so turns the body’s natural tumour suppressing mechanisms “back on” to kill the cancer cells.
Restoring a function
“We designed the nanoparticles so that they protect the mRNA from degradation, prolong mRNA circulation in blood and improve cellular uptake and cytosolic transport,” says study lead author Mohammad Islam. “The circulating mRNA nanoparticles enter tumour tissue thanks to the naturally leaky vasculature of the tumour. They are then internalized by the cancer cells for efficient mRNA transfection.”
“Most conventional cancer therapies are designed to block something, such as pro-tumorigenic drivers, for instance,” adds co-team leader Bruce Zetter of Boston’s Children Hospital. “Our approach is different in that it restores a function – in this case the lost tumour suppressors. It could thus complement current cancer treatments for correcting both pro-tumorigenic and tumour-supressing pathways at the same time.”
“Since loss of tumour-suppressor function is highly correlated with tumour growth and metastasis, the technique might lead to the development of new types of precision medicine for treating cancer,” Shi tells Physics World.
“Exciting times”
“These are exciting times for the field of nucleic acid therapeutics with the recent regulatory approval of the first siRNA therapeutics and numerous mRNA treatments under clinical investigation,” adds co-team leader Omid Farokhzad, of BWH.
The researchers, reporting their work in Nature Biomedical Engineering s41551-018-0284-0, say they are now busy looking into additional tumour suppressors, such as p53, using their nanoparticle-mediated mRNA delivery strategy. “We also plan to combine this approach with other therapies for more effective overall cancer treatment,” says Shi.
