Exploitation of the Apoptosis-Primed State of MYCN-Amplified Neuroblastoma to Develop a Potent and Specific Targeted Therapy Combination

Exploitation of the Apoptosis-Primed State of MYCN-Amplified Neuroblastoma to Develop a Potent and Specific Targeted Therapy Combination
Ham, J, (2016) Cancer Cell (Link to abstract)

 

This group used a drug screen to identify two molecules (ABT-263 and ABT-199) that inhibit growth in MYCN-amplified neuroblastoma cell lines. Through several lines of evidence, they show that MYCN amplification makes cells more prone to apoptosis and that apoptosis can be triggered by inhibiting BCL-2 as these molecules do. They then show that the degree of apoptosis is even greater when these molecules are combined with alisertib (an Aurora Kinase inhibitor) which seems to further reduce the apoptosis threshold in these cells. They finally show that the combination of these drugs induces sustained remission in xenograft mouse models. None of these effects are seen in wild type MYCN neuroblastoma.


* This is the first study to show quite conclusively that MYCN can be targeted with clinically available drugs. Alisertib has already been tested in phase I/II studies in neuroblastoma alone and in combination with irinotecan/ temozolamide; the barriers to testing this combination in humans will be lower than usual. As always, a mouse xenograft is not the same as a spontaneous arising human tumor so we should still maintain a level of skepticism in the face of these optimistic results.