Abstract B46: Targeting pancreatic cancer organoids with dual BET and CBP/P300 inhibitor NEO2734
Bibliographic record
Abstract
Abstract Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis due to largely ineffective therapeutics available for this disease. Recently, inhibitors of bromodomain and extraterminal domain (BET) inhibitors have been shown to have therapeutic efficacy against various malignancies, including PDA. Here we present data on sensitivity of PDA patient-derived organoids (PDO) to a novel dual BET and CBP/P300 inhibitor, NEO2734 (Epigene Therapeutics Inc.). Our cell viability screen on a panel of 30 PDOs derived from PDA patient and xenograft tumor tissue revealed differential drug sensitivities to NEO2734 inhibitor. Antitumor effect of NEO2734 on the most sensitive PPTO.2 model was further confirmed in vivo using patient-derived xenograft PPTO.2 model. To identify potential biomarkers associated with differential sensitivities of PDA PDOs to NEO2734 inhibitor, we generated gene expression profiles from 13 PDOs derived from primary patient tumors. Using the probabilistic concordance index (C-index), 13 genes (Bonferroni corrected P<1.0E-10) were identified as potential therapeutic targets. Among the biomarkers identified, we found three associations with known BET inhibitor target genes, including CA9 (C-index= 0.38, PBonferroni= 2.7E-19), which is known to be downregulated by BET inhibitor and coexpressed with the target gene BRDT. Furthermore, the biomarker SLC7A2 (0.28, 3.4E-37) has a known genetic interaction with BRD4, and ABCB6 (0.31, 1.5E-27) is predicted to be coexpressed with CREBBP. Overall, this work reveals that dual BET and CBP/P300 inhibitor, NEO2734, could be a novel therapeutic option for a subset of PDA patients. Citation Format: Nikolina Radulovich, Laura Tamblyn, Heewon Seo, Benjamin Haibe-Kains, Mathieu Lupien, Francis Gilles, Ming S. Tsao. Targeting pancreatic cancer organoids with dual BET and CBP/P300 inhibitor NEO2734 [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B46.
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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".