Functional Precision Medicine Identifies New Therapeutic Candidates for Medulloblastoma

Abstract

◥Medulloblastoma is among the most common malignant brain tumors in children. Recent studies have identified at least four subgroups of the disease that differ in terms of molecular characteristics and patient outcomes. Despite this heterogeneity, most patients with medulloblastoma receive similar therapies, including surgery, radiation, and intensive chemotherapy. Although these treatments prolong survival, many patients still die from the disease and survivors suffer severe long-term side effects from therapy. We hypothesize that each patient with medulloblastoma is sensitive to different therapies and that tailoring therapy based on the molecular and cellular characteristics of patients' tumors will improve outcomes. To test this, we assembled a panel of orthotopic patient-derived xenografts (PDX) and subjected them to DNA sequencing, gene expression profiling, and high-throughput drug screening. Analysis of DNA sequencing revealed that most medulloblastomas do not have actionable mutations that point to effective therapies. In contrast, gene expression and drug response data provided valuable information about potential therapies for every tumor. For example, drug screening demonstrated that actinomycin D, which is used for treatment of sarcoma but rarely for medulloblastoma, was active against PDXs representing Group 3 medulloblastoma, the most aggressive form of the disease. Functional analysis of tumor cells was successfully used in a clinical setting to identify more treatment options than sequencing alone. These studies suggest that it should be possible to move away from a one-size-fits-all approach and begin to treat each patient with therapies that are effective against their specific tumor.Significance: These findings show that high-throughput drug screening identifies therapies for medulloblastoma that cannot be predicted by genomic or transcriptomic analysis.

Small-molecule screen reveals synergy of cell cycle checkpoint kinase inhibitors with DNA-damaging chemotherapies in medulloblastoma

“…Short tandem repeat analysis and sequencing of previously reported genetic alterations confirmed the identity of all cell lines. DNA methylation array, MYC expression, or TP53 mutation was used to determine molecular subgroup (55). D283 MB cells have been reported as both G3 and G4 (56-58), but our data classify them as G3-II.…”

Systems pharmacogenomics identifies novel targets and clinically actionable therapeutics for medulloblastoma

“…By identifying how the network of interacting genes and proteins cooperate to dictate drug response, we can use patterns in the network to target therapy. Pharmacogenomics approaches have shown benefit in other cancers [ 13 , 14 ]; however, the scarcity of actionable mutations in MB has historically limited the application of genomics for drug selection [ 15 ]. The development of a computational strategy for prioritizing candidate drugs represents an alternative approach to rapidly evaluate existing therapeutics against a computational model prior to moving to experimental work.…”

Investigating the Central Nervous System Disposition of Actinomycin D: Implementation and Evaluation of Cerebral Microdialysis and Brain Tissue Measurements Supported by UPLC-MS/MS Quantification

“…Nevertheless, comprehensive information on its central nervous system (CNS) disposition is lacking. However, previous studies suggested a potential role of actinomycin D in the treatment of pediatric CNS neoplasms: Preclinical studies revealed efficacy in in vitro models of ependymoma [ 15 ] and, to a certain degree, in orthotopic mouse models of glioblastoma, medulloblastoma, and embryonal tumors with multilayered rosettes (ETMR) [ 16 , 17 , 18 ]. Therefore, our aim was to establish a suitable experimental setup to accurately determine the still unclear CNS disposition of actinomycin D. This setup combined quantification of actinomycin D by ultraperformance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) in cerebral microdialysis microsamples from freely moving mice with measurements in brain tissue and plasma.…”