It has been shown that p53 binding targets include both high-affinity binding sites, including cell-cycle arrest targets, and low-affinity sites, including apoptotic targets, are activated at low and high thresholds of p53-pathway activation, respectively.15,18 Since therapeutic activation of p53 leads to the successful treatment of SHH-MBs, we propose that the recent de-escalation trials failed to generate sufficiently high levels of p53-pathway activation to induce apoptosis, and consequently, fail to eliminate Sox2+ cells (Figure 6F). Here, SOX2 is linked to Mobius syndrome.