A lucky circumstance led scientists, working in mice, to discover that nanoparticle-delivered siRNA blockers of a molecule found in ovarian cancer can dramatically improve response to chemotherapy.
The siRNA molecules blocked the production of EGFR (epidermal growth factor receptor), which is linked to particularly aggressive cancers.
The study, “Targeted in vivo delivery of EGFR siRNA inhibits ovarian cancer growth and enhances drug sensitivity,” was published in the journal Scientific Reports.
The goal of the Georgia Institute of Technology research team’s experiments was to test if the delivery system, composed of a nanohydrogel, was effective in delivering siRNAs to a tumor in mice. They had only tested the system in a lab dish earlier, and chose to use EGFR as it is known to contribute to cancer growth and is easy to measure.
The nanohydrogel is essentially a tiny pellet, composed of a compact organic molecule and 98 percent water. The gel contains a molecule that allows it to gather at the site of the tumor by binding to a receptor.
Once there, siRNA strands, loaded onto the gel, enter the cells and bind to mRNA, which is an intermediate molecule between a gene and a protein. In this way, the siRNA prevents the production of the targeted factor.
Researchers loaded siRNA molecules, labeled with a fluorescent dye, onto the nanohydrogel, and gave it to mice carrying human ovarian cancers. The mice were then treated with Platinol (cisplatin), the most commonly used chemotherapeutic for ovarian cancer.
While control animals also benefitted from the chemotherapy, its effect in mice who got Platinol together with siRNA against EGFR was impressive.
“The dramatic effect we see is the massive reduction or complete eradication of the tumor, when the ‘nanohydrogel’ treatment is given in combination with existing chemotherapy,” John McDonald, senior author of the study, said in a news release.
But there is room for caution. The study only involved four mice treated with the combination of chemotherapy and siRNA, so more preclinical studies are needed. “Further work will be required to see if the treatment completely destroyed every trace of cancer cells in the tumors that disappeared, or if future recurrence is possible,” said McDonald.
Nevertheless, scientists have had their eyes on EGFR for a long time. A high number of receptors on tumor cells make them resistant to chemotherapy by blocking apoptosis, or programmed cell death. Researchers have tried treating patients with drugs that block certain aspects of EGFR signaling, but only about 20 percent of patients benefit from such an approach.
Using siRNA prevents EGFR to be made in the tumor in the first place, and so blocks all aspects of its actions. It appears that doing so allows the chemotherapy to turn cell death pathways on again, but as EGFR acts on tumor cells in multiple ways, researchers are not yet sure how exactly the treatment manages to do the good that’s been seen.