Abstract A007 DNA damage response deficiency enhances neuroblastoma progression and sensitivity to combination PARP and ATR inhibition
Bibliographic record
Abstract
Abstract Background: Significant progress has been made in identifying mutations and defining biological heterogeneity in neuroblastoma (NB) using high-throughput sequencing approaches. However, functional roles for many specific genetic alterations in NB initiation, growth, and metastasis remain to be fully defined. Pathogenic and/or likely pathogenic (P/LP) alterations in genes involved in DNA Damage Response (DDR) pathways were identified in approximately 30% of patients enrolled in the SickKids Cancer Sequencing Program (KiCS). Despite being well studied in many adult cancers, roles for DDR disruption and potential therapeutic implications remains poorly understood for NB and other pediatric solid tumors. Aims: We aimed to define roles for DDR-deficiency in NB progression and assess the therapeutic potential of targeted agents using patient-specific DDR loss-of-function NB models. Methods: We incorporated loss-of-function mutations in atm, brca2, palb2, and bard1 into an established zebrafish MYCN-driven model of human NB and characterized tumor progression, transcriptional signatures, and response to candidate therapeutics in vivo. Human cell lines with DDR protein knock-down were used to assess candidate drug combinations in vitro. Results: Mutations in DDR genes were found to enhance tumor penetrance and metastasis in MYCN-driven zebrafish NB, and resulted in upregulation of proliferation, cell cycle checkpoint, and DNA damage repair transcriptional signatures. Zebrafish DDR-deficient NB and human NB cells with DDR protein knock-down were sensitive to the poly(ADP-ribose)-polymerase (PARP) inhibitor olaparib, and this effect was further enhanced by inhibition of the ataxia telangiectasia and rad3 related (ATR) kinase. Conclusions: Our data supports an in vivo functional role for DDR-deficiency in NB, as well as potential molecular vulnerabilities. Pre-clinical assessments in vitro and in vivo suggest therapeutic potential for combination PARP + ATR inhibition in NB patients with alterations in DDR genes. Citation Format: Madeline N. Hayes, Sarah Cohen-Gogo, Lynn Kee, Mehdi Layeghifard, Ivette Valencia-Sama, Anisha Rajaselvam, David Kaplan, Anita Villani, Adam Shlien, Daniel A. Morgenstern, Meredith S Irwin. DNA damage response deficiency enhances neuroblastoma progression and sensitivity to combination PARP and ATR inhibition [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A007.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".