Abstract B117: Treatment of castrated resistant prostate cancer with EPI-7386, a second generation N-terminal domain androgen receptor inhibitor
Bibliographic record
Abstract
Abstract Background: The androgen receptor (AR) pathway drives most metastatic castration-resistant prostate cancers (mCRPC) even in late stages of the disease and resistance to ligand binding domain (LBD)-linked therapies inevitably emerges. Mechanisms of resistance to anti-androgens include AR gene amplification, C-terminal ligand-binding domain (LBD) mutations and expression of constitutively-active truncated AR splice variants lacking the LBD (e.g. AR-V7). Inhibition of the N-terminal domain (NTD) of the AR can inhibit transcriptional activity even in the presence of LBD-driven resistance. A Phase I clinical trial of the first-generation AR NTD inhibitor, EPI-506, demonstrated minor PSA declines in anti-androgen refractory mCRPC patients, revealing the need for more potent and metabolically stable NTD inhibitors. EPI-7386 represents a second generation of NTD inhibitors (Anitens) that are more active and more metabolically stable than EPI-506. Methods: Chemical structure activity relationships were explored to increase molecule potency while maintaining target specificity using a wide variety of CRPC models in vivo and in vitro. The stability and selectivity of the molecules were characterized with a panel of selective screening and functional assays. The mechanism of action and pathway engagement markers were followed by qPCR and RNAseq. Results: EPI-7386 was chosen as the IND candidate. The molecule demonstrated a 20-fold improvement in AR-driven cellular potency compared to EPI-002, while being highly stable in human and animal hepatocytes. In vitro proliferation assays demonstrated on-target activity across a panel of prostate cancer cell lines, with activity demonstrated in AR-V7-driven cellular models. The antiproliferative effect correlated with the inhibitory effect on AR driven genes, including specifically AR-V7 driven genes such as UBE2C. EPI-7386 controlled tumor growth and induced tumor regressions in several CRPC xenografts, including AR-V7-driven 22Rv1 and enzalutamide resistant LNCaP95 models, as well as the VCaP model. Importantly, the combination of enzalutamide with EPI-7386 demonstrated a more robust and consistent PSA and antitumor response in the VCaP model. EPI-7386 was well tolerated in animal models, and therapeutic levels could be achieved without displaying signs of toxicity in a 14-day rat study. Pharmacodynamic markers will be presented, in addition to their incorporation in the future clinical plan. Conclusions: The next generation aniten compound EPI-7386 is more active and metabolically stable than EPI-506. It shows on-target activity in AR full length and AR-V7 driven models, and demonstrates a high therapeutic index in preclinical models. As a single agent, EPI-7386 may overcome anti-androgen clinical resistance in advanced mCRPC as well as potentially in combination therapy with anti-androgens in earlier stages of the disease. The clinical strategy supporting the development of this Aniten N-terminal domain inhibitor of AR will be discussed. Citation Format: Ronan Le Moigne, C. Adriana Banuelos, Nasrin R Mawji, Teresa Tam, Jun Wang, Kunzhong Jian, Raymond J Andersen, Alessandra Cesano, Marianne D Sadar, Han-Jie Zhou, Peter Virsik. Treatment of castrated resistant prostate cancer with EPI-7386, a second generation N-terminal domain androgen receptor inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B117. doi:10.1158/1535-7163.TARG-19-B117
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.000 | 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 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".