Abstract Current standard of care for medulloblastoma (MB) consists of surgical resection followed by craniospinal irradiation and chemotherapy; however, survivors often suffer long-term morbidity. Identifying novel therapeutic targets is critical to enhance survival and reduce treatment-related toxicity. Using a dataset of 1350 MB samples, we identified significant upregulation of the RNA/DNA binding protein Y-box binding protein 1 (YBX1) in MB compared to normal cerebellum. Clinically, high YBX1 expression correlates with poorer overall survival, serving as a negative prognostic indicator. Functionally, CRISPR-Cas9 knockout of YBX1 led to decreased proliferation, downregulation of the oncogenic driver MYC, and a significant enhancement of animal survival in orthotopic MB models. These findings establish a regulatory function for YBX1 critical for tumor maintenance. To exploit this, we utilized SU056, a YBX1 antagonist that targets tumor cell proliferation and rebalances stemness and differentiation genes. While SU056 monotherapy showed limited efficacy in orthotopic patient-derived xenograft models, it presented a potent opportunity for rational combinations. Recently, YBX1 was identified as a key regulator of homologous recombination (HR)-mediated DNA repair in MB. We found that YBX1 KO cells are highly sensitive to radiotherapy (RT). In our studies, SU056 demonstrated potent synergy with RT across multiple primary MB models and reversed radioresistance in relapsed models. Critically, in p53-deficient SHH cells—characterized by extreme radioresistance—SU056 reversed resistance and induced apoptosis, evidenced by increased sub-G1 populations. Mechanistically, SU056 impaired DNA damage response (DDR) kinetics, resulting in persistent gH2AX foci and increased micronuclei post-RT, confirming a failure to repair lethal double-strand breaks. In vivo, SU056 significantly extends survival of orthotopic tumor-bearing animals when combined with radiation. In summary, YBX1 is a critical dependency in MB that regulates the MYC axis and DNA repair. Pharmacological inhibition of YBX1 with SU056 abrogates the DNA repair capacity of tumor cells, suggesting clinical utility in both frontline and relapse settings for children with aggressive, treatment-refractory medulloblastoma.
Evans et al. (Tue,) studied this question.