Past decades have seen dramatic improvements in survival rates for children with blastomas. However, given the long-term toxic effects of genotoxic drugs, there remains a strong clinical need to explore new therapeutic options, which are more efficacious yet associated with minimal late effects. Therefore, re-activation of p53 via targeted, nongenotoxic approaches is an attractive therapeutic strategy.
To correct abnormal miRNA expression, miRNA modulation by replacing/forcing expression of suppressor miRNAs or inhibiting oncogenic miRNAs using antagomirs has been tested in blastomas. Suppression of oncogenic miR-380-5p and miR-125b in in-vivo models of mouse neuroblastoma and zebrafish brain resulted in the increase of p53 protein and subsequent apoptosis [54,55]. Conversely, transfection with tumor-suppressive miRNAs (Let-7 miRNA mimics or miR-34a) resulted in cellular differentiation and diminished tumor growth as a result of apoptosis and DNA synthesis suppression in both neuroblastoma and retinoblastoma models [62,104,105]. However, despite promising results in preclinical models, miRNA-mediated therapies have not entered mainstream cancer therapy and still require further refinement to minimize off-target effects .
High expression of AURKA has shown oncogenic properties in human cancers, including neuroblastoma. Cell culture and xenograft experiments have indicated that treating neuroblastoma by depleting AURKA using shRNA or inhibitors (CCT137690 and MLN8237) leads to significant tumor growth inhibition [107–109]. Some AURKA inhibitors including MK-5108 and MLN8237 have undergone Phase I and II clinical trials (NCT00543387, NCT02444884, NCT01154816) in patients with advanced/refractory and recurrent neuroblastoma as a single agent or in combination with existing chemotherapies (Table 2). It is worth noting that concomitant inhibition of Mdm2-p53 and Aurora kinase acts synergistically to induce p53-dependent apoptosis in acute myelogenous leukemia, and may be efficacious in neuroblastoma as well .
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