Antitumor Activity and Bone Regeneration: Tackling Multiple Angles of Osteosarcoma

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Fiona Freeman, PhD, assistant professor, University College Dublin, discussed her research into microRNA-29b in suppressing tumor growth and promoting bone remodeling in mice models.

Preclinical findings published in Advanced Materials have demonstrated the potential of microRNA (miR)-29b to suppress tumor growth and promote bone remodeling. The research comes out of University College Dublin and demonstrated miR-29b's potential in animal models of osteosarcoma. When miR-29b was delivered along with systemic chemotherapy, mice had a significant decrease in tumor burden, an increase in survival, and a significant decrease in osteolysis compared to chemotherapy alone.

CGTLive spoke with the study's first author Fiona Freeman, PhD, assistant professor, University College Dublin, to learn more about the new research and its findings. She gave an overview of the research her lab conducted in mice models of osteosarcoma with lung metastases and touched on further research she would like to do with miR-29b.

CGTLive: Can you go over your findings in mice models of osteosarcoma?

Fiona Freeman, PhD: The animal model of osteosarcoma we used is quite representative of what would happen in clinic. And so we allowed the tumor to form for two weeks. And then after that, we wanted to deliver our miRNAs. We developed a hyaluronic acid-based hydrogel system to deliver the miRNAs directly to the tumor site. And so it's a , and so and it also it crosslinks in situ. So it allowed us to non-invasively inject in the hydrogel around the tumor without having to open the mice open and inject it in and it also showed with fluorescent labeling that the nanoparticles were being released only around the tumor site, and for 14 days. We could see a significant reduction in tumor growth in the mice where we delivered the miRNA, which wasn’t seen with only chemotherapy. However, when we brought it out to long term survival, there was significantly better survival when you combine the miRNA with the chemotherapy.

We had an antitumor response, but the next thing we wanted to see was what was happening to the bone tissue since this particular miRNA can also help with bone regenerative capabilities. We looked at the CT scans of the mice before therapy, and then 2, 4, and 8 weeks post therapy. And so, what we found was that the tibial plateau in the mice treated with the miRNA plus doxorubicin had significantly better retention of the tibial plateau. There was a significant reduction in osteolysis compared to chemotherapy or the non-treated groups alone. We also compared it with BMP2 growth factor and when we delivered BMP2 without doxorubicin, there was an increase in bone regenerative capabilities, however, the tumor grew way faster. When we delivered BMP2 plus doxorubicin, that regenerative capacity was completely reduced. However, when we delivered the miRNA compared to the BMP2, we saw a significant reduction in tumor volume, as well as the significant increase in bone regeneration, and so that was really exciting.

What other avenues would you like to explore with this research?

We did use a really aggressive lung metastases model, so although we had a significant increase in survivability, a lot of the animals did succumb to the disease due to the presence of lung metastases. So now we're ind of looking at trying to see if there's a better way of delivering this miRNA or whether we should try and deliver it as miRNA along with another therapeutics like immunotherapy and that could be delivered systemically, so we could attack the tumor locally and then attack the tumor systemically in a different way.

Something that was really surprising was the anti-apoptotic effect is very selective. It's only in the cancer cells and we didn't really see itin anything else. When we deliver this miRNA to healthy cells, there was absolutely no apoptotic effect. But when we delivered it to the cancer cells, there was a significant selective apoptotic effect, which I think is really interesting. We wanted to delve into that a bit further and see why that is, and so we found that the miRNA seems to induce inhibition of BCL2, and it's slight upregulation of BAX genes, which is, I believe, indicative of intrinsic apoptosis. And so that was kind of interesting and could be a genetic target for other different types of cancers.

This content has been edited for clarity.

REFERENCE
Freeman FE, Dosta P, Shanley LC, et al. Localized nanoparticle-mediated delivery of miR-29b normalizes the dysregulation of bone homeostasis caused by osteosarcoma whilst simultaneously inhibiting tumor growth. Adv. Mater. 2023; 35(23):2207877. doi: 10.1002/adma.202207877
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