Abstract A22: YAP1 knockout in vitro models of medulloblastoma showed improved response to sonidegib
Bibliographic record
Abstract
Abstract Background: Medulloblastoma (MB) is the most common malignant brain tumor in childhood. Despite improvement in current treatment, children still suffer from long-term sequelae resulting from standard care therapy. World Health Organization considers MB as 4 distinct entities: SHH, WNT, Group 3, and Group 4. The most aggressive variant of SHH MB is the bearer of TP53 mutation and it is resistant to standard chemo/radiation therapy. Therefore, novel treatments modalities are urgently needed. In this study we aimed to evaluate the biologic relevance of YAP1 in SHH MB human cell lines bearers of TP53 mutation and its potential as a new therapeutic target. Methods: We generated YAP1 CRISPR/CAS9 knockout single-cell clones of human cell lines DAOY and UW228 assigned as “MB SHH-like” and bearers of TP53 mutation. We picked sonidegib as a standard-care chemotherapy for in vitro SHH MB model and assessed the apoptosis/necrosis using Annexin V/Propidium-Iodide staining to identify positive cells through flow cytometry. Proliferation and colony formation were assessed by cell counting Kit 8 proliferation assay and GIEMSA staining, respectively. Additionally, we used verteporfin, a YAP1 inhibitor, and evaluated its effect on cell proliferation. Findings: Using single-cell cloning, we successfully generated DAOY and UW228 cell lines with depleted YAP1 protein. YAP1 knockout cell lines DAOY and UW228 showed improved response to sonidegib regarding i) decrease in proliferation (p<0.05), ii) apoptosis induction (p<0.01), and iii) colony formation abrogation (p<0.001). In order to step towards translation, we tested verteporfin (YAP1 inhibitor) and found that this compound successfully reduced proliferation in both cell lines (p<0.05). Conclusion: Although YAP1 depletion showed association with better response to sonidegib, a smoothened inhibitor, more experiments are needed to evaluate if the in vitro findings might shed new light on a potential synergistic combination between sonidegib and verteporfin and provide a good rationale for targeted therapy. Citation Format: Gustavo Alencastro Veiga Cruzeiro, Taciani de Almeida Magalhães, Graziella de Sousa Ribeiro, Pablo Ferreira das Chagas, Ricardo Bonfim Silva, Sampurna Chatterje, Carlos Alberto Scrideli, Luiz Gonzaga Tone. YAP1 knockout in vitro models of medulloblastoma showed improved response to sonidegib [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A22.
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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) | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".