Abstract 5050: KCNJ2 constitutes a marker and therapeutic target of high-risk medulloblastomas.
Bibliographic record
Abstract
Abstract Medulloblastoma comprises the most common malignant brain tumor in children. Non-WNT/SHH tumors define the most refractory medulloblastoma subgroups. Interestingly, 17q gain, the most common genetic aberration in medulloblastoma, comprises a cytogenetic hallmark of these molecular high-risk tumors detected in group 3 (62%), and group 4 (73%). The majority of recurrent tumors harbor 17q gain in the corresponding primary. Virtually all of these tumors develop resistance to current treatment protocols at relapse. The lack of a common molecular target hampers the development of urgently needed novel treatment strategies. Through mRNA expression profiling of 64 primary tumor samples, we identified potassium inwardly-rectifying channel J2 (KCNJ2) as one of the most upregulated genes on chromosome 17q in tumors with 17q gain. High KCNJ2 transcript levels were significantly associated with non-WNT/non-SHH grouping, anaplastic histology, metastatic dissemination, and poor clinical outcome. KCNJ2 protein expression was analyzed by immunohistochemistry in a large cohort of patients (n=199), and high protein expression levels were found to be strongly correlated with 17q gain, metastatic dissemination, and inferior prognosis (p<0.0001). To functionally validate the potential role of KCNJ2 in medulloblastoma biology, we performed knockdown experiments by small interfering RNA-mediated silencing in two well-characterized medulloblastoma cell lines. Transient knockdown of KCNJ2 resulted in a reduced proliferation rate and induction of apoptosis. Furthermore, treatment of the medulloblastoma cell lines and medulloblastoma stem cells with amiodarone and gambogic acid, two inhibitors of this class of Kir channels, phenocopied these effects in a time- and dose-dependent manner. Whole cell patch clamp results revealed a nearly complete current blockade upon inhibitor treatment. Subsequently, we showed that pharmacological inhibition of KCNJ2 and knockdown KCNJ2 significantly reduced tumor growth and resulted in prolonged survival in an orthotopic medulloblastoma mouse model. In summary, our data suggest that pharmacological inhibition of KCNJ2 may constitute a new therapeutic option for patients with high-risk medulloblastomas. Citation Format: Francesca Valdora, Florian Freier, Livia Garzia, Vijay Ramaswamy, Claudia Seyler, Thomas Hielscher, Nathan Brady, Paul A. Northcott, Marcel Kool, David TW Jones, Hendrik Witt, Gian Paolo Tonini, Wolfram Scheurlen, Hugo A. Katus, Andreas E. Kulozik, Edgar Zitron, Andrey Korshunov, Peter Lichter, Michael D. Taylor, Stefan M. Pfister, Marc Remke. KCNJ2 constitutes a marker and therapeutic target of high-risk medulloblastomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5050. doi:10.1158/1538-7445.AM2013-5050
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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".