Abstract 610: Preclinical evaluation of novel androgen receptor N-terminal domain inhibitor EPI-002 for the treatment of castration-resistant prostate cancer
Bibliographic record
Abstract
Abstract Background: Androgen receptor (AR) is a ligand-activated transcription factor that plays critical roles in lethal and incurable castration-resistant prostate cancer (CRPC). EPI-002 is a novel small molecule that specifically targets the AR N-terminal domain (NTD), while conventional therapies target the ligand-binding domain (LBD). Our previous work suggests that EPI-002 may have clinical potential to treat CRPC. Here, the objective was to evaluate EPI-002 against several clinically relevant conditions such as elevated expression of AR co-activators, variable lengths of the poly-glutamine tract (CAG-repeats) within AR NTD, and constitutively active AR splice variants lacking the LBD. Methods: To evaluate the effect of EPI-002 on AR transcriptional activity against overexpressed co-activators such as SRC1-3 and p300, luciferase reporter assays were performed using LNCaP cells transfected with an AR-driven reporter and various amounts of the co-activators. AR-negative COS1 cells were employed for reporter assays to examine if the length of CAG-repeats (varying from 0 to 49) affects EPI-002 inhibition. The effect of EPI-002 on constitutively active AR splice variants was studied in LNCaP95 cells, which express endogenous AR-V7 variant. The expression of several genes regulated by AR-V7 was analyzed by QPCR in LNCaP95 cells treated with antiandrogen enzalutamide or EPI-002. The proliferation of LNCaP95 cells treated with EPI-002 was measured using BrdU incorporation. The efficacy of EPI-002 on LNCaP95 xenografts was studied in castrated male mice by oral delivery and compared to control and enzalutamide. Results: EPI-002 effectively inhibited AR transcriptional activity in spite of overexpressed co-activators SRC1, SRC2, SRC3, or p300. The variable lengths of CAG-repeats within the NTD had no effect on the inhibition of AR by EPI-002. In LNCaP95 cells, EPI-002 significantly blocked the transcriptional activity of AR-V7 indicated by decreased levels of mRNA of AR-V7 regulated genes such as UBE2C. In contrast, enzalutamide had no effect on expression of these genes. EPI-002 significantly inhibited the androgen-independent and antiandrogen-resistant proliferation of LNCaP95 cells. In castrated male mice, EPI-002 attenuated the growth of LNCaP95 xenografts, whereas enzalutamide had no significant effect. By the end of the 28-day study, animals treated with EPI-002 had xenografts that were half of the size of those from the control arm. Conclusions: AR NTD inhibitor EPI-002 was effective against several clinically relevant conditions, including overexpressed co-activators, variable lengths of CAG-repeats, and constitutively active AR-V7. These findings support EPI-002 as a promising therapeutic agent to treat CRPC, particularly against castration-resistant tumors driven by constitutively active AR splice variants that are resistant to LBD-targeting therapies. Citation Format: Yu Chi (Kevin) Yang, Nasrin (Rina) Mawji, Jean Wang, Marianne Sadar. Preclinical evaluation of novel androgen receptor N-terminal domain inhibitor EPI-002 for the treatment of castration-resistant prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 610. doi:10.1158/1538-7445.AM2014-610
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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) | 0.004 | 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".