Abstract 5831: Activated Wnt signaling for the treatment of recurrent 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 targeting by small molecules and transgenic patient-derived lines containing a stabilized beta-catenin mutant. Activated Wnt signaling by way of Wnt agonists in treatment-refractory MBs resulted in decreased in vitro self-renewal and promoted differentiation. Comparative gene expression profiling of control and transgenic lines containing a stabilized beta-catenin mutant demonstrated a reduction in stem cell self-renewal genes following beta-catenin overexpression, including Sox2 and Bmi1. 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 mice with orthotopic injections of cells containing a stabilized beta-catenin mutant representative of constitutively active Wnt signaling or endogenous Wnt-active cells. Xenografts generated from Wnt-activated tumors were smaller in size, maintained a lower rate of proliferation, and reduction in MB self-renewal genes. To further illustrate the clinical utility of activated Wnt signaling, we modified the Children’s Oncology Group therapy protocol for childhood MB so that xenografts may receive chemo/radiotherapy. Tumors generated from Wnt-active xenografts were much more radiosensitive and displayed a significant reduction in spinal metastasis when compared to mice receiving standard therapy without Wnt activation. To develop a rationale clinical therapeutic, we developed unique agonist antibodies that target the Wnt co-receptor LRP5. Treatment with LRP5 antibodies showed a significant reduction in tumor burden and increase in survival of patient-derived tumors that were otherwise treatment-resistant. Our work establishes for the first time 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. Note: This abstract was not presented at the meeting. Citation Format: Branavan Manoranjan, Chitra Venugopal, Zvezdan Pavlovic, David Bakhshinyan, Michelle Kameda-Smith, Minomi Subapanditha, Sujeivan Mahendram, Jason Moffat, Bradley W. Doble, Sheila Singh. Activated Wnt signaling for the treatment of recurrent medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5831. doi:10.1158/1538-7445.AM2017-5831
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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) | 0.001 | 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".