Activity of NEO2734, a novel dual inhibitor of both BET and CBP-P300, in SPOP-mutated prostate cancer.
Bibliographic record
Abstract
62 Background: We have previously reported that mutations in SPOP promote bromodomain and extra-terminal motif (BET) protein upregulation and BET inhibitor resistance in prostate cancer (Zhang et al., Nature Medicine 23(9):1055-1062, 2017). Other studies indicate that histone acetyltransferases (HATs) such as P300 are also upregulated in SPOP-mutated prostate cancer (Blattner et al., Cancer Cell 31: 436-451, 2017). Methods: We examined the anti-cancer effect of NEO2734 (Epigene Therapeutics Inc), a novel dual inhibitor of both BET and CBP-P300, in prostate cancer using cell line, organoid and patient-derived xenografts (PDX) as working models. We examined the anti-cancer effect of NEO2734 (Epigene Therapeutics Inc), a novel dual inhibitor of both BET and CBP-P300, in prostate cancer using cell line, organoid and patient-derived xenografts (PDX) as working models. Results: We demonstrated that while prostate cancer cell lines expressing F133V, the most frequent SPOP mutant, are very resistant to both BET inhibitor JQ1 and CBP/P300 inhibitor CPI-637, they are very sensitive to simultaneous cotreatment with JQ1 and CPI-637. Similarly, we demonstrated that F133V mutant cells are also very sensitive to NEO2734. We established PDX and organoid models from a patient with prostate cancer expressing a novel SPOP mutation Q165P. Computer simulation analysis reveals that the Q165P mutation causes larger conformational fluctuation, indicating that the structure of Q165P is less stable than that of wild type SPOP. Accordingly, co-immunoprecipitation assay showed that Q165P mutation impaired the dimerization ability of SPOP. We further showed that the Q165P mutant organoid was very sensitive to NEO2734 in vitro and the Q165P mutant PDX was very sensitive to NEO2734 in mice. Conclusions: These PDX-based pre-clinical studies indicate that the inhibition of both BET and CBP-P300, either by co-administration of two agents, or by treatment with the dual inhibitor, NEO2734, is effective in SPOP-mutated prostate cancer. These data provide a strong rationale for the inclusion of patients with SPOP-mutated prostate cancer in clinical studies of NEO2734.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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) | 0.000 | 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 teacher head, 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".