Mechanistic insights into medulloblastoma relapse.

Pediatric brain tumors are the leading cause of cancer-related deaths in children, with medulloblastoma (MB) being the most common type. A better understanding of these malignancies has led to their classification into four major molecular subgroups. This classification not only facilitates the stratification of clinical trials, but also the development of more effective therapies. Despite recent progress, approximately 30% of children diagnosed with MB experience tumor relapse. Recurrent disease in MB is often metastatic and responds poorly to current therapies. As a result, only a small subset of patients with recurrent MB survive beyond one year. Due to its dismal prognosis, novel therapeutic strategies aimed at preventing or managing recurrent disease are urgently needed. In this review, we summarize recent advances in our understanding of the molecular mechanisms behind treatment failure in MB, as well as those characterizing recurrent cases. We also propose avenues for how these findings can be used to better inform personalized medicine approaches for the treatment of newly diagnosed and recurrent MB. Lastly, we discuss the treatments currently being evaluated for MB patients, with special emphasis on those targeting MB by subgroup at diagnosis and relapse.

Triptolide and its pro-drug Minnelide target high-risk MYC amplified medulloblastoma in preclinical models.

Most children with medulloblastoma (MB) achieve remission, but some face very aggressive metastatic tumors. Their dismal outcome highlights the critical need to advance therapeutic approaches that benefit such high-risk patients. Minnelide, a clinically relevant analog of the natural product triptolide, has oncostatic activity in both preclinical and early clinical settings. Despite its efficacy and tolerable toxicity, this compound has not been evaluated in MB. Utilizing a bioinformatic dataset that integrates cellular drug response data with gene expression, we predicted that Group 3 (G3) MB, which has a poor five-year survival, would be sensitive to triptolide/Minnelide. We subsequently showed that both triptolide and Minnelide attenuate the viability of G3 MB cells ex vivo. Transcriptomic analyses identified MYC signaling, a pathologically relevant driver of G3 MB, as a downstream target of this class of drugs. We validated this MYC dependency in G3 MB cells and showed that triptolide exerts its efficacy by reducing both MYC transcription and MYC protein stability. Importantly, Minnelide acted on MYC to reduce tumor growth and leptomeningeal spread, which resulted in improved survival of G3 MB animal models. Moreover, Minnelide improved the efficacy of adjuvant chemotherapy, further highlighting its potential for the treatment of MYC-driven G3 MB patients.

Noncanonical activation of GLI signaling in SOX2+ cells drives medulloblastoma relapse.

SRY (sex determining region Y)-box 2 (SOX2)-labeled cells play key roles in chemoresistance and tumor relapse; thus, it is critical to elucidate the mechanisms propagating them. Single-cell transcriptomic analyses of the most common malignant pediatric brain tumor, medulloblastoma (MB), revealed the existence of astrocytic Sox2+ cells expressing sonic hedgehog (SHH) signaling biomarkers. Treatment with vismodegib, an SHH inhibitor that acts on Smoothened (Smo), led to increases in astrocyte-like Sox2+ cells. Using SOX2-enriched MB cultures, we observed that SOX2+ cells required SHH signaling to propagate, and unlike in the proliferative tumor bulk, the SHH pathway was activated in these cells downstream of Smo in an MYC-dependent manner. Functionally different GLI inhibitors depleted vismodegib-resistant SOX2+ cells from MB tissues, reduced their ability to further engraft in vivo, and increased symptom-free survival. Our results emphasize the promise of therapies targeting GLI to deplete SOX2+ cells and provide stable tumor remission.