Systems pharmacogenomics identifies novel targets and clinically actionable therapeutics for medulloblastoma

Abstract

Background Medulloblastoma (MB) is the most common malignant paediatric brain tumour and a leading cause of cancer-related mortality and morbidity. Existing treatment protocols are aggressive in nature resulting in significant neurological, intellectual and physical disabilities for the children undergoing treatment. Thus, there is an urgent need for improved, targeted therapies that minimize these harmful side effects. Methods We identified candidate drugs for MB using a network-based systems-pharmacogenomics approach: based on results from a functional genomics screen, we identified a network of interactions implicated in human MB growth regulation. We then integrated drugs and their known mechanisms of action, along with gene expression data from a large collection of medulloblastoma patients to identify drugs with potential to treat MB. Results Our analyses identified drugs targeting CDK4, CDK6 and AURKA as strong candidates for MB; all of these genes are well validated as drug targets in other tumour types. We also identified non-WNT MB as a novel indication for drugs targeting TUBB, CAD, SNRPA, SLC1A5, PTPRS, P4HB and CHEK2. Based upon these analyses, we subsequently demonstrated that one of these drugs, the new microtubule stabilizing agent, ixabepilone, blocked tumour growth in vivo in mice bearing patient-derived xenograft tumours of the Sonic Hedgehog and Group 3 subtype, providing the first demonstration of its efficacy in MB. Conclusions Our findings confirm that this data-driven systems pharmacogenomics strategy is a powerful approach for the discovery and validation of novel therapeutic candidates relevant to MB treatment, and along with data validating ixabepilone in PDX models of the two most aggressive subtypes of medulloblastoma, we present the network analysis framework as a resource for the field.

No strong association among epigenetic modifications by DNA methylation, telomere length, and physical fitness in biological aging

“…Moreover, the same study found that longer-lived cell lineages have an active X chromosome with a longer telomere than the inactive X, indicating that telomere maintenance alleles on the X chromosome impact survival. It was also suggested that the male Y chromosome is less protected and more prone to telomere shortening, but the chromosome-dependent telomere shortening is under debate (Genovesi et al 2021). The results of the current study could not demonstrate that in the given population females have longer telomeres than males.…”

Association among epigenetic modifications by DNA methylation, telomere length, and physical fitness in biological aging

“…Moreover, the same study found that longer lived cell lineages have an active X chromosome with longer telomere than the inactive X, indicating that telomere maintenance alleles on X chromosome impact survival. It was also suggested that in male Y chromosome is less protected and more prone to telomere shortening, but the chromosome dependent telomere shortening is under debate (Genovesi et al 2021). The results of the current study could not demonstrate that at the given population females have longer telomere than males.…”

Food insecurity as a risk factor of sarcopenic obesity in older adults

“…Sarcopenia and obesity share pathological factors, including aging, changes in BC, inflammation, and hormones ( 27 ). The aging process carries a low metabolic rate and metabolic adaptations, including adaptive thermogenesis and changes in oxidative capacity; this process favors the development and onset of SO ( 28 ). Changes in BC related to age are the main risk factor for SO.…”