RNA Therapy Switches Off Cancer Cells’ “Chemical GPS”
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A new study shows that an RNA nanoparticle can prevent the spread of multiple myeloma (MM), a type of bone marrow cancer, in mice. The therapy, administered either alone or in combination with an FDA-approved MM drug, also reduced tumor burden and increased survival in mice. The research is published in PNAS.
Treating an incurable disease
Bone marrow is a spongy tissue found inside some of our bones such as the femur, pelvis and spine. Cells within the bone marrow produce blood cells, and MM affects a type of white blood cell called plasma cells. These produce antibodies that help to fight infection.
Affected cells in MM produce abnormal proteins that have negative effects on the rest of the body such as the kidneys and can also affect the production of red blood cells and platelets. MM spreads rapidly throughout the body and quickly mutates, making treatment difficult.
The disease is incurable and was responsible for over 100,000 deaths worldwide in 2020. Patients with advanced MM that has become resistant to chemotherapy typically survive for just six to nine months.
New and innovative therapies are needed to improve the survival of those affected by MM. To this end, researchers from the University of Pennsylvania School of Engineering and Applied Science created an RNA nanoparticle therapy that can “switch off” the pathways that MM cells use to spread around the body.
Switching off the “chemical GPS”
This new treatment turns off a cancer-attracting signal in endothelial cells – a major part of the bone marrow microenvironment – to make it more difficult for MM cells to spread.
Endothelial cells produce a protein called cyclophilin A (CyPA) that helps to fold and transport proteins as well as activate T cells when we are sick. In people with MM, endothelial cells can produce too much CyPA. This attracts MM cells into the bone marrow and helps them to spread, much like a “chemical GPS.”
“To stop the spread, we aimed to turn off this function of CyPA using RNA therapy, targeting the microenvironment of the cancer instead of the cancer cell itself,” said Dr. Michael Mitchell, associate professor of bioengineering and co-senior author of the study. “But getting nucleic acids into the marrow was challenging due to the complex biological barriers.”
This meant that the researchers had to redesign the vehicle that delivers the RNA nanoparticle to enable it to enter the bone marrow and shut off the CyPA signal.
“We designed a new hybrid nanoparticle that could deliver small interfering RNA (siRNA) to endothelial cells,” said Christian Figueroa-Espada, lead author of the study and PhD student at the University of Pennsylvania. “The siRNA stops cells from producing CyPA. When tested in vitro, the therapy prevented the spread of cancer cells. When tested in mice, both alone and in combination with chemotherapies, our therapy was able to decrease the size of tumors, extend survival rates and decrease the cancer’s resistance to chemotherapy.”
A promising treatment prospect
This research holds the potential to remove a longstanding barrier in MM treatment by blocking its spread around the body.
“This work can help improve current treatments for multiple myeloma as well as other cancers that spread through the blood vessels,” Mitchell added. “Using our platform for targeted nanoparticle development, we are looking forward to investigating other cancers and diseases where CyPA is overexpressed.”
Future work for the team includes identifying other potential targets for this type of therapy, as well as investigating the possibility of silencing additional functions in cancer microenvironments to overcome cancer initiation, spread and drug resistance. With additional studies in larger animals proving its safety, the RNA nanoparticle therapy may move forward to clinical trials in humans.
Reference: Guimarães PPG, Figueroa-Espada CG, Riley RS, et al. In vivo bone marrow microenvironment siRNA delivery using lipid–polymer nanoparticles for multiple myeloma therapy. PNAS. 2023;120(25):e2215711120. doi: 10.1073/pnas.2215711120
This article is a rework of a press release issued by the University of Pennsylvania. Material has been edited for length and content.