The researchers developed a nanoparticle carrying a molecular marker that binds to the surface of cancer cells, triggering the cells to absorb it. The siRNA carried within the particle was designed to silence a gene called ribonucleotide reductase M2 (RRM2), which regulates DNA synthesis and repair and is known to be an anticancer target. Because it was the first trial using targeted RNAi delivery for cancer, says Mark Davis, a professor of chemical engineering at Caltech and the study’s lead author, “we wanted to choose a gene that was suspected to be hugely upregulated in a broad spectrum of cancers” in order to increase the likelihood of being able to observe the novel therapy’s effect.
The researchers analyzed biopsy samples from three melanoma patients in the trial who had received different doses of the therapy. They tracked the particles in the different samples, finding that the amounts they could see in the tumor cells correlated with the doses the patients received. “That’s the first time anyone has seen that for any kind of particle delivery system, whether it’s a liposome, a nanoparticle, or anything,” says Davis. They also pulled out samples of mRNA cleaved exactly where the siRNA’s were designed to cut, showing that the RNAi did its job the way it was expected to. The study does not discuss the clinical effects of the treatment on the melanoma patients in the trial; that data, says Davis, will be presented at the meeting of the American Society of Clinical Oncology in early June. The trial was sponsored by Calando Pharmaceuticals, a California-based startup founded by Davis that is developing nanoparticle-based siRNA therapies for cancer.
The trial is a promising start, say researchers, but much remains to do before such therapies are truly ready for clinical use. “It’s a small but important first step,” says Judy Lieberman, a professor of pediatrics at Harvard University working on RNAi delivery. “Getting delivery into a peripheral tumor in the skin is very good news.” She cautions, though, that it’s difficult to draw conclusions from just three patients. “I don’t think you can make a dose-dependent statement based on three samples.” Also, she notes, the authors didn’t report the therapy’s effects on molecular features in the tumor cells themselves, such as cell proliferation or apoptosis.
“There’s much more data to be collected,” says Sharp, who was also a cofounder of and remains a scientific advisor to Alnylam Pharmaceuticals, a biotech company developing RNAi therapeutics. “What’s so hard about this set of data is, yes, they see some nanoparticles there, but is it enough?” Indeed, notes Mark Kay, director of the Program in Human Gene Therapy at Stanford University, past work suggests that even when a drug makes it into the correct cell, “a large proportion of it doesn’t go into a biologically active compartment” where it can fulfill its therapeutic task. And ultimately, Kay says, “what is still missing–not just from this study but from all studies–is [demonstrating] efficacy of RNAi to treat diseases.”