Stop the spread: a novel siRNA nanotherapy for multiple myeloma
Novel therapeutic delivered to the multiple myeloma tumor microenvironment in the bone marrow inhibits key pathway in the metastasis of the disease.
A recent research effort from the University of Pennsylvania (PA, USA) has developed a promising therapeutic for the management of multiple myeloma. The RNA-based therapeutic, packaged in a novel nanoparticle delivery system, could be a vital tool in preventing the rabid spread associated with the cancer, dramatically improving outcomes for patients.
Multiple myeloma spreads rapidly from its primary site in the bone marrow, metastasizing and differentiating throughout the body. This makes it one of the deadliest forms of cancer, taking the lives of over 100,000 people a year, typically in less than 6 months after diagnosis for the chemo-refractory version of the disease. Currently, there is no cure and designing treatments that can keep up with the frenetic spread and differentiation of the cancer is highly challenging.
One of the mechanisms responsible for the rapid spread of multiple myeloma relies on the overexpression of the protein cyclophilin A (CyPA) from endothelial cells lining blood vessels in bone marrow. In healthy tissue, CyPA is responsible for protein folding and transport as well as T-cell activation. In the tumor microenvironment, CyPA is overexpressed and secreted in the blood, where it acts as a homing factor, attracting multiple myeloma cells from the bone marrow into the blood. Once in the blood, the cancer cells can spread quickly around the body.
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Spotting this pathway as a potential chink in the armor of multiple myeloma, the team set out to design a small interfering RNA (siRNA)-based therapeutic to inhibit it and stop the cancer metastasizing. To overcome the nefarious biological barriers preventing nucleic acids from accessing the bone marrow, the team first had to design a new delivery system for the siRNA.
Discussing the design, co-first author Christian Figueroa-Espada stated that, “we designed a new hybrid nanoparticle that could deliver small interfering RNA (siRNA) to endothelial cells.” The team deployed combinatorial chemistry and high-throughput in vivo screening methods to design the lipid–polymer nanoparticle.
Once designed, the team tested their therapy in vitro and in a mouse model. Their in vitro experiments clearly demonstrated that CyPA was inhibited in epithelial cells in bone marrow, preventing the movement of cancer cells. In the mouse model, the therapy was tested solo and as an adjuvant therapy to chemotherapy. In both of these indications, the therapy extended survival and decreased tumor size, even improving chemotherapy response when used simultaneously.
This therapy could prove vital for the future of multiple myeloma treatment if it can make it through clinical trials, and the team have not missed the opportunity it could present for other cancers that metastasize through the blood. “Using our platform for targeted nanoparticle development, we are looking forward to investigating other cancers and diseases where CyPA is overexpressed,” noted senior author Michael Mitchell.
