Abstract 148: Canonical Wnt activation as a therapeutic strategy in pediatric medulloblastoma
Bibliographic record
Abstract
Abstract Brain tumors represent the leading cause of childhood cancer mortality, of which medulloblastoma (MB) is the most frequent malignant pediatric brain tumor. Current molecular subgroups of MB recognize distinct disease entities of which activated Wnt signaling (monosomy 6, exon 3 mutations in CTNNB1, and Wnt gene signature) is associated with a distinct subgroup and the best overall outcome. In contrast, only non-Wnt MBs are characterized by metastatic disease, increased rate of recurrence, and poor overall survivorship. Given the excellent clinical outcome in patients with Wnt-driven MB, we aimed to convert treatment-resistant MB subgroups into an ostensibly benign tumor through selective activation of the canonical Wnt pathway. Initial characterization of patient-derived Wnt and non-Wnt MB lines demonstrated a significant reduction in in vitro self-renewal and proliferative capacity of Wnt MBs. This was further validated by RNA-seq, which identified a marked reduction in the expression of stem cell self-renewal genes Bmi1 and Sox2 in Wnt MBs compared to non-Wnt MBs. Further, Wnt MB-derived xenografts maintained a significant increase in overall survival compared to non-Wnt MB xengrafts, further highlighting the protective nature of activated Wnt signaling in MB. Activated Wnt signaling by way of small molecule Wnt agonists in treatment-refractory MBs resulted in decreased in vitro self-renewal and expression of self-renewal genes, Bmi1 and Sox2. In order to validate the therapy-sensitive nature of Wnt-activated cells, we developed stable patient-derived lines containing a 7XTOPFlash reporter for endogenous Wnt signaling. Rare subclonal Wnt-active cells demonstrated a reduced self-renewal and tumor-initiating capacity through in vivo limiting dilution assays when compared to bulk Wnt-inactive cells. The therapeutic relevance of these findings were demonstrated with an in vivo survival advantage in those mice with orthotopic injections of cells with endogenous Wnt activity when compared to xenografts generated from Wnt-inactive cells. To develop a rationale clinical therapeutic, we used a novel substrate-competitive peptide inhibitor for GSK. Treatment with our peptide inhibitor showed a significant reduction in tumor burden with a corresponding increase in survival of patient-derived tumors that were otherwise treatment-resistant. The clinical utility of our findings is further supported by our analysis of integrated genomics data from 763 primary MBs, in which a validated Wnt gene signature was found to predict improved survivorship among children with poor-outcome and metastatic MBs. Our work establishes activated Wnt signaling as a novel treatment paradigm in childhood MB, identifies a rationale therapeutic approach for recurrent MB, and provides evidence for the context-specific tumor suppressive function of the canonical Wnt pathway. Citation Format: Sheila Kumari Singh, Branavan Manoranjan, Anna Dvorkin-Gheva, Chitra Venugopal, Steven Moreira, Michelle Kameda-Smith, Minomi Subapanditha, Ashley Adile, David Bakhshinyan, Neil Savage, Blake Yarascavitch, Olufemi Ajani, Adam Fleming, Bradley Doble. Canonical Wnt activation as a therapeutic strategy in pediatric medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 148.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".