Michael D Taylor | PubMed Health

PubMed2025

Carbonic Anhydrase Inhibition Sensitizes Group 3 Medulloblastoma to Radiotherapy.

UNLABELLED: Group 3 (G3) medulloblastoma constitutes the most aggressive molecular subgroup, and nearly all patients present with metastases upon recurrence. Treatment for newly diagnosed medulloblastoma relies on a combination of maximal safe surgical resection, followed by chemotherapy and ionizing radiation, and no therapies have been shown to confer a survival benefit at the time of recurrence. Given the limited therapeutic options available for patients with medulloblastoma, especially at recurrence, and the incomplete understanding of the molecular mechanisms underlying resistance to treatment, we sought to uncover actionable targets and biomarkers that could help refine patient selection and treatment of newly diagnosed medulloblastoma to reduce the risk of recurrence. In clinically relevant mouse models of G3 medulloblastoma, CT-guided fractionated radiotherapy extended overall survival and induced the clonal selection of radioresistant subpopulations of tumor cells that drove medulloblastoma recurrence. Comparison of recurrent tumors with treatment-naïve newly diagnosed tumors revealed a gene expression signature that was found to be a biomarker of radioresistance and poor prognosis. This prognostic gene signature was shown to be subgroup specific in a large patient cohort. Recurrent tumors had elevated expression of carbonic anhydrase 4, and genetic and pharmacologic modulation of carbonic anhydrase 4 could promote or reduce resistance to radiotherapy. These data suggest that the FDA-approved carbonic anhydrase inhibitor acetazolamide may be a useful radiosensitizer to improve the efficacy of the treatment of newly diagnosed G3 medulloblastoma that could reduce the risk of tumor recurrence and improve survival in pediatric patients. SIGNIFICANCE: G3 medulloblastoma features a prognostic subgroup-specific gene expression signature and can be targeted with a carbonic anhydrase inhibitor to enhance radiosensitivity, reducing the risk of recurrence and improving survival.

Medulloblastoma↗

PubMed2023

3D genome mapping identifies subgroup-specific chromosome conformations and tumor-dependency genes in ependymoma.

Ependymoma is a tumor of the brain or spinal cord. The two most common and aggressive molecular groups of ependymoma are the supratentorial ZFTA-fusion associated and the posterior fossa ependymoma group A. In both groups, tumors occur mainly in young children and frequently recur after treatment. Although molecular mechanisms underlying these diseases have recently been uncovered, they remain difficult to target and innovative therapeutic approaches are urgently needed. Here, we use genome-wide chromosome conformation capture (Hi-C), complemented with CTCF and H3K27ac ChIP-seq, as well as gene expression and DNA methylation analysis in primary and relapsed ependymoma tumors, to identify chromosomal conformations and regulatory mechanisms associated with aberrant gene expression. In particular, we observe the formation of new topologically associating domains ('neo-TADs') caused by structural variants, group-specific 3D chromatin loops, and the replacement of CTCF insulators by DNA hyper-methylation. Through inhibition experiments, we validate that genes implicated by these 3D genome conformations are essential for the survival of patient-derived ependymoma models in a group-specific manner. Thus, this study extends our ability to reveal tumor-dependency genes by 3D genome conformations even in tumors that lack targetable genetic alterations.

Child↗