Abstract B029: Studies in human bone cell co-cultures reveal a potential mechanism underlying bone fractures in children treated with entrectinib and suggest a positive association with vitamin D
Bibliographic record
Abstract
Abstract Introduction: Entrectinib, a NTRK, ROS1 and ALK inhibitor, approved in the US for adult patients with ROS1-positive metastatic non-small cell lung cancer and adult and pediatric patients older than 1 month of age with solid tumors that have a NTRK gene fusion, has been associated with the occurrence of bone fractures, particularly in pediatric patients. These fractures might be caused by an inhibition of signaling pathways relevant for bone development in children. Methods: To investigate the mechanism of the observed effect we used a suite of human bone cells representing both juvenile and adult bone physiology. These models were treated with Entrectinib and its major metabolite M5. Molecular as well as functional readouts were assessed to reveal the pathomechanism of the observed clinical findings. Results: Data showed, that Entrectinib induced a reduction of cellular markers of osteoblastic activity and a reduced formation of mineralized matrix. Conversely, Entrectinib had stimulating effects on osteoclast function indicative of bone resorption. 3D osteoblast-osteoclast cultures revealed decreased stiffness after Entrectinib treatment, confirming the cell signaling data. These findings were particularly pronounced in the absence of 17β-estradiol, characteristic for juvenile bone. Finally, pre-treatment with Vitamin D led to partially restored osteoblast function in vitro, while osteoclast function was suppressed. Conclusions: These experiments support the suspected on-target effect of Entrectinib underlying increased fractures in children with developing bone, offering potential mitigation strategies once these observations have been confirmed with clinical data. Citation Format: Sabrina Ehnert, Kevin A. Schulz, Alison K. Cardenas, Georgina Meneses-Lorente, Adrian Roth, Sabine Fürst-Recktenwald. Studies in human bone cell co-cultures reveal a potential mechanism underlying bone fractures in children treated with entrectinib and suggest a positive association with vitamin D [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 B029.
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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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 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".