Leveraging Medulloblastoma Clonal Dynamics to Overcome Treatment Resistance.
AI interpretation is pending for this paper.
Open original publication →What the AI sees
Not AI summarized yet.
Research significance
Pending deeper interpretation.
Source abstract
PURPOSE: Medulloblastoma is a common pediatric brain tumor with distinct molecular subgroups. Among them, group 3 medulloblastoma is associated with increased recurrence, metastatic potential, and poor patient outcomes. Small-molecule inhibitors targeting B cell-specific Moloney murine leukemia virus insertion site 1 (BMI1) have demonstrated efficacy against several types of malignant tumors, including pediatric medulloblastoma. Although our previously published in vivo study provided a promising proof of concept for the therapeutic targeting of BMI1 in group 3 medulloblastoma with small-molecule inhibitors, it is not sufficient to eradicate the tumor. EXPERIMENTAL DESIGN: In this study, following preclinical validation of BMI1 inhibitor PTC596, DNA barcoding technology was leveraged to profile in vivo clonal dynamics of group 3 medulloblastoma in response to the established chemoradiotherapy regimen alone and in combination with PTC596. Following demonstration of a small number of treatment-refractory clones, we sought to identify potential druggable molecular vulnerabilities by utilizing phosphoproteomic profiling and genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screening. RESULTS: By comparing the changes in the phosphorylation pattern of key signaling kinases after PTC596 treatment with the list of sensitizer genes from in vitro genome-wide CRISPR/CRISPR-associated protein 9 screen and with the essential genes in human neural stem cells, we identified several context-specific regulators of mTOR, AKT, and PLK1 pathways. Subsequently, targeting the PI3K pathway with enzastaurin was most amenable to synergistic targeting alongside BMI1 inhibition. CONCLUSIONS: This work provides the foundation for clinical validation of small-molecule inhibitors synergistic with PTC596 to improve the durability of remissions and extend the survival of patients with treatment-refractory group 3 medulloblastoma.