Temporal profiling of therapy resistance in human medulloblastoma identifies novel targetable drivers of recurrence
David Bakhshinyan1,2, Ashley A Adile1,2, Jeff Liu3
1McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada.
Abstract:
Medulloblastoma (MB) remains a leading cause of cancer-related mortality among children. The paucity of MB samples collected at relapse has hindered the functional understanding of molecular mechanisms driving therapy failure. New models capable of accurately recapitulating tumor progression in response to conventional therapeutic interventions are urgently needed. In this study, we developed a therapy-adapted PDX MB model that has a distinct advantage of generating human MB recurrence. The comparative gene expression analysis of MB cells collected throughout therapy led to identification of genes specifically up-regulated after therapy, including one previously undescribed in the setting of brain tumors, bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4). Subsequent functional validation resulted in a markedly diminished in vitro proliferation, self-renewal, and longevity of MB cells, translating into extended survival and reduced tumor burden in vivo. Targeting endothelial nitric oxide synthase, a downstream substrate of BPIFB4, impeded growth of several patient-derived MB lines at low nanomolar concentrations.
Insights
Researchers developed a new medulloblastoma model to study therapy failure. They identified a gene, BPIFB4, that when targeted, significantly reduced tumor growth and improved survival in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Pediatric Cancer Research
Background:
- Medulloblastoma (MB) is a primary pediatric brain tumor with high mortality.
- Lack of relapsed MB samples hinders understanding of treatment resistance.
- Novel models are needed to study MB recurrence and therapy failure.
Purpose of the Study:
- To develop a therapy-adapted patient-derived xenograft (PDX) medulloblastoma model.
- To identify molecular mechanisms of MB recurrence after therapy.
- To investigate BPIFB4 as a potential therapeutic target.
Main Methods:
- Development of a therapy-adapted PDX MB model for studying recurrence.
- Comparative gene expression analysis of MB cells during therapy.
- In vitro and in vivo functional validation of BPIFB4 and its downstream targets.
Main Results:
- The PDX model successfully recapitulated human MB recurrence.
- Bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4) was identified as upregulated post-therapy.
- BPIFB4 inhibition reduced MB cell proliferation, self-renewal, and tumor burden in vivo.
- Targeting endothelial nitric oxide synthase, a BPIFB4 substrate, showed potent anti-MB activity.
Conclusions:
- The therapy-adapted PDX MB model is valuable for studying treatment failure.
- BPIFB4 plays a critical role in MB recurrence and progression.
- Targeting BPIFB4 or its downstream pathways offers a promising therapeutic strategy for medulloblastoma.
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