With a worldwide incident rate of 3.4 cases per million people per year, osteosarcoma is one of the most common bone cancers affecting children and adolescents. The current gold standard treatment option requires extensive surgical intervention and chemotherapy that leads to a poor prognosis and decreased quality of life. Due to the aggressive nature of the disease, the surgical intervention usually involves total reconstruction of the limbs or, in most cases, amputation. Researchers at Brigham and Women's Hospital, a founding member of the Mass General Brigham healthcare system, in collaboration with investigators at University College Dublin (UCD), Massachusetts Institute of Technology (MIT), and Trinity College Dublin (TCD), have identified a potential therapeutic target and developed a unique delivery system to treat osteosarcoma. In a preclinical study, the team found that using microRNA nanoparticles delivered locally using a hydrogel suppressed osteosarcoma growth while simultaneously decreasing bone damage. Results are published in Advanced Materials.
"The standard-of-care treatment plan today is no different compared to when first introduced almost 50 years ago," said lead author Fiona Freeman, PhD, an assistant professor at UCD School of Mechanical and Materials Engineering and Fellow at UCD Conway Institute, who completed the study during her Marie Skłodowska-Curie Global Fellowship in the Artzi lab at the Brigham and MIT. "Nearly one third of patients relapse and need new interventions. This unmet clinical need prompted us to focus on the possible use of microRNA therapy in osteosarcoma, and specifically on a genetic target called miR-29b."
In their study, the researchers explored the therapeutic potential of miR-29b, a microRNA they hypothesized could block osteosarcoma tumor growth. MicroRNAs are a family of molecules that help control certain activities in cells like growth and development. They are showing promising results in the treatment of cancer and viral infection. The team developed a formulation of miR-29b nanoparticles that were delivered via a hyaluronic-based hydrogel delivery system directly to the tumor site. The hyaluronic-based injectable delivery system turned to gel at the target area of the body in a matter of minutes and allowed for local and sustained delivery of the miR-29b to the primary tumor site.
"This work seeks to answer an important basic science question, as to the balance between being able to regenerate damaged bone so that these young patients will not lose their limbs while preventing tumor recurrence," said senior author Natalie Artzi, PhD, of the Brigham's Department of Medicine. "Our study demonstrates the power of local delivery—the miR-29b loaded nanoparticles improve the therapeutic potential of chemotherapy and suppress tumor growth, while simultaneously aiding in the repair of the surrounding damaged bone even while the patient is undergoing chemotherapy treatment."
In addition to evaluating whether the gene therapy approach could decrease tumor growth, the investigators also assessed whether the therapy could normalize the dysregulation of bone growth. Both chemotherapeutics and osteosarcoma tumors have been shown to disrupt bone's ability to repair following surgical intervention.
In a mouse model of osteosarcoma, the researchers compared the addition of the hydrogel gene therapy with chemotherapy to chemotherapy alone. The team found that when miR-29b was delivered along with systemic chemotherapy, the therapy provided a significant decrease in tumor burden, an increase in mouse survival, and a significant decrease in the destruction of the bone caused by the tumor. The research team also validated the therapeutic potential using two predictive models of the disease; a 3D co-culture spheroid model; and an orthotopic metastatic murine model.
This work highlights the importance of leveraging biomaterials to enhance the therapeutic window of therapies that would not be able to reach the target site in adequate amounts because of premature degradation or systemic toxicity. By doing so, the mechanisms associated with the therapy can be studied and the right drug combination and timed release can be realized. The team's approach may enable, in the future, the delivery of immune modulating agents that can be leveraged to train the immune system to prevent cancer recurrence—a major problem in osteosarcoma patients.
The research team is committed to building on this research and advancing this technology towards clinical application. Studies like this multi-institutional collaboration show the promise of gene therapy for treating conditions like osteosarcoma and other difficult-to-treat cancers. Mass General Brigham recently launched its Gene and Cell Therapy Institute to help translate scientific discoveries made by researchers like Artzi, Freeman and colleagues into first-in-human clinical trials and, ultimately, life-changing treatments for patients.
This project was conducted in the Artzi lab in collaboration with researchers within the laboratory of Daniel Kelly at Trinity College Dublin, Ireland. Freeman spent three years between these two laboratories conducting a Marie Skłodowska-Curie Global Fellowship.
"Fiona's findings have the potential to revolutionize cancer treatment and improve outcomes by providing vital information that can inform the design of future combination therapies for these young patients," said Kelly, a professor in Tissue Engineering at Trinity College Dublin and Amber principal investigator, who was co-author of the paper.
Funding: This work was funded by the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie Grant Agreement No. 839150 and the Gillian Reny Stepping Strong Center for Trauma Innovation.
Paper cited: Freeman, F. E. et al. "Localized Nanoparticle-Mediated Delivery of miR-29b Normalises the Dysregulation of Bone Homeostasis Caused by Osteosarcoma Whilst Simultaneously Inhibiting Tumour Growth." Advanced Materials, DOI:10.1002/adma.202207877.
