Abstract
Rhabdomyosarcomas are the most common pediatric soft tissue sarcoma and are a major cause of death from cancer in young patients requiring new treatment options to improve outcomes. High-risk patients include those with metastatic or relapsed disease and tumors with PAX3-FOXO1 fusion genes that encode a potent transcription factor that drives tumourigenesis through transcriptional reprogramming. Polo-Like Kinase-1 (PLK1) is a serine/threonine kinase that phosphorylates a wide range of target substrates and alters their activity. PLK1 functions as a pleiotropic master regulator of mitosis and regulates DNA replication after stress. Taken together with high levels of expression that correlate with poor outcomes in many cancers, including rhabdomyosarcomas, it is an attractive therapeutic target. This is supported in rhabdomyosarcoma models by characterization of molecular and phenotypic effects of reducing and inhibiting PLK1, including changes to the PAX3-FOXO1 fusion protein. However, as tumor re-growth has been observed, combination strategies are required. Here we review preclinical evidence and consider biological rationale for PLK1 inhibition in combination with drugs that promote apoptosis, interfere with activity of PAX3-FOXO1 and are synergistic with microtubule-destabilizing drugs such as vincristine. The preclinical effects of low doses of the PLK1 inhibitor volasertib in combination with vincristine, which is widely used in rhabdomyosarcoma treatment, show particular promise in light of recent clinical data in the pediatric setting that support achievable volasertib doses predicted to be effective. Further development of novel therapeutic strategies including PLK1 inhibition may ultimately benefit young patients with rhabdomyosarcoma and other cancers.
Highlights
Rhabdomyosarcomas (RMS) are the most common pediatric soft tissue sarcoma and are a major cause of death from cancer in young patients
In cancer cell lines and xenograft models including fusion positive RMS it has been noted that reduction of Polo-Like Kinase-1 (PLK1) expression or its inhibition leads to mitotic arrest which can lead to apoptosis [22,23,24]
The potential contribution of targeting the fusion protein via PLK1 inhibition is consistent with the known effects of modulating PAX3-FOXO1 expression levels on growth arrest, myogenic differentiation, migration and invasion as well as potentially apoptosis [17]
Summary
Rhabdomyosarcomas (RMS) are the most common pediatric soft tissue sarcoma and are a major cause of death from cancer in young patients. PLK1 inhibitors both alone and in combination with other agents are considered, including the effects targeting PLK1 has on the PAX3-FOXO1 fusion protein. In cancer cell lines and xenograft models including fusion positive RMS it has been noted that reduction of PLK1 expression or its inhibition leads to mitotic arrest which can lead to apoptosis [22,23,24].
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