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To develop 3D bioPRINTed osteoinductive constructs that deliver CHEMOtherapeutics within large bone defects that are surgically created when removing bone tumours.

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Double hit on osteosarcoma: tumour suppression and bone repair

Osteosarcoma therapy is due for an upgrade. Combined delivery of chemotherapy alongside localised gene therapy reduces tumour growth and promotes bone healing.

Digital Economy
Health

Every year over 3 million children and adolescents are diagnosed with the bone tumour osteosarcoma. Patients who are diagnosed with osteosarcoma today will receive the same standard-of-care regimen that was first introduced in the late 1970s: tumour resection and chemotherapy. However, nearly one third of patients relapse, necessitating new interventions. Osteosarcoma tumours are inextricably linked to their local microenvironment, composed of bone, stromal, vascular and immune cells. This microenvironment is now considered to be essential for tumour growth and a potential target for the design of novel therapies.

In vitro 3D osteosarcoma model

Recently, there has been increased interest in the use of 3D cultures to study the complexity of the tumour microenvironment, as they are more predictive of the in vivo situation. Towards this goal, scientists of the PRINT-CHEMO project developed a novel 3D model of osteosarcoma containing a co-culture of mesenchymal stromal cells and osteosarcoma cells using a hydrogel microwell system. The research was undertaken with the support of the Marie Skłodowska-Curie Actions (MSCA) programme and involved the production of tumour spheroids that modelled early and late osteosarcoma stages. These showed great potential for high-throughput drug screening. “Our osteosarcoma model provides a unique platform for screening potential therapeutic options and concentrations of drugs for both early and late-stage osteosarcoma,” outlines the MSCA research fellow Fiona Freeman.

Supporting bone regeneration in osteosarcoma patients

Following surgical resection of the tumour, the bone of patients must be regenerated. The use of tissue engineering strategies for this purpose remains controversial. Moreover, although chemotherapy is effective in controlling cancer cell growth, it also significantly hinders the bone’s ability to regenerate. Therefore, any strategy that would enhance bone regeneration would be of great interest to these young patients. To address this issue, PRINT-CHEMO investigated the therapeutic potential of microRNA-29b, known for its role in promoting bone formation by inducing osteoblast differentiation and also for suppressing prostate and glioblastoma tumour growth. Researchers assessed whether localised delivery of microRNA-29b suppressed osteosarcoma tumour growth and offered the necessary cues for repair. MicroRNAs were complexed with nanoparticles and delivered locally via an injectable system in a preclinical model of osteosarcoma. Researchers observed that the combination of microRNA-29b and systemic chemotherapy, compared to chemotherapy alone, led to a 45 % decrease in tumour burden, a significant increase in survival, and a 75 % reduction in tumour-associated bone osteolysis. This anticancer and pro-osteogenic effect of microRNA-29b delivery may extend to other types of cancer. “Our results demonstrate not only the therapeutic potential of localised microRNA delivery in osteosarcoma tumour suppression but also its potential to aid bone repair after surgery,” emphasises Freeman.

Extending therapeutic benefit for bone metastases

The PRINT-CHEMO novel combinatorial therapy can easily be integrated into the current regimen of conventional chemotherapy to further improve clinical outcome. Bone is one of the most common locations of cancer cell metastasis. Therefore, any therapy that inhibits bone tumour growth whilst simultaneously aiding in bone regeneration would be of significant benefit. This extends beyond osteosarcoma to any cancer patient with bone metastases.

Keywords

PRINT-CHEMO, osteosarcoma, chemotherapy, microRNA-29b, bone regeneration, tumour suppression, bone metastases, mesenchymal stromal cells, 3D model

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