Investigation of Therapeutic Vulnerabilities in Metastatic Neuroblastoma
Bibliographic record
Abstract
Survival for high-risk neuroblastoma (NB) remains poor. Most patients who recur present with metastatic disease, and few targetable pathways governing metastatic spread to distant sites are known, thus, novel approaches to target metastatic NB are required. We previously developed a metastatic mouse model to select cells with enhanced ability to spread to the bone and brain and identified a signature based on differentially expressed genes, which also predicted patient survival. To discover new NB therapies, we first utilized the Connectivity Map platform to identify compounds that can reverse this metastatic transcriptional signature. We identified calcipotriol, a Vitamin D3 analog, to be a compound that selectively targets cell lines with enhanced metastatic potential. Our studies demonstrated that following calcipotriol treatment proliferation of metastatic, but not parental, cells was reduced. Survival via Vitamin D Receptor (VDR) signaling increases the expression of RASSF2, a negative regulator of the Hippo signaling pathway, and reduces the levels of the Hippo pathway effectors, YAP and TAZ. RASSF2 is required for the antitumor effects of calcipotriol and for the reduction of levels and nuclear localization of YAP/TAZ. Migration of the enhanced metastatic cells and YAP/TAZ levels are reduced after calcipotriol treatment and YAP overexpression reduces calcipotriol sensitivity. Furthermore, metastatic cells that overexpress VDR also showed lower tumor burden in vivo, thus indicating that VDR signaling pathway may be a novel therapeutic target in metastatic and high-risk NB. Finally, in other efforts to identify novel targets for high-risk metastatic NB, genomic sequencing studies have revealed frequent mutations in DNA damage response (DDR) genes in NB tumors. We demonstrate that PARP inhibition (PARPi) results in growth inhibition of a subset of NB cell lines with high MYCN expression. In addition, knockdown of the DDR genes, BRCA1/2 and PALB2, sensitizes resistant MYCN non-amplified NB cells to PARPi through increased accumulation of DNA damage. Together, these results provide a rationale for further investigation and potential therapeutic targeting of two novel pathways, Vitamin D signaling and DNA damage response, in metastatic relapsed NB.
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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".