Abstract A080: Establishment and characterization of a panel of prostate cancer XPDX models with differential AR-V7 staining and enzalutamide response

Abstract

Abstract Background: Truncated androgen receptor splice variant-7 (AR-V7) expression is associated with prostate cancer progression and resistance to AR-directed therapy. To better understand the role of AR-V7 in prostate cancer, we compared IHC-based AR-V7, full length AR and PSMA protein expression in 9 prostate adenocarcinoma (PAC) XPDX and 5 prostate neuroendocrine tumors (PNEC) XPDX models and correlated expression to in vivo sensitivity to enzalutamide. Variability in receptor expression and in vivo enzalutamide sensitivity was further examined in PAC XPDX models when implanted into alternate mouse strains, intact versus castrated (/CX) animals or when conditioned with enzalutamide. Methods: The PAC parental XPDX models ST1273, ST2347 and ST4017 have been previously described, while ST4420, ST6838 and STM344 are newly established. ST1273/EZR, ST2347/EZR and ST4017/EZR are PAC models conditioned with enzalutamide in vivo to manifest enzalutamide drug resistance. Evaluated PNEC XPDX models included ST072, ST072B, ST2403, ST4005C and STM002. All models were characterized using WES and RNAseq and tested for AR-V7, AR and PSMA receptor expression. For in vivo studies, enzalutamide was administered once daily by oral gavage. Endpoints included tumor volume and time from treatment initiation with %T/C values and tumor regression reported at study completion; a T/C of ≤ 20% versus control was considered sensitive. Tumor regression (%T/C<0%) versus Day 0 tumor volume was also reported. Results: PAC and PNEC models were successfully passaged and tested in SCID and nude strains. Most PAC models were AR+/PSMA+ except ST6838 (-/+) and STM344 (-/-); staining was maintained regardless of mouse strain, castration status or enzalutamide conditioning. PNEC models were AR-/PSMA- except ST2403 (-/+). Two PAC models were intrinsically positive for AR-V7, ST4017, established from a patient post ABI/ENZA and ST6838 from a treatment-naïve patient. No PNEC models were AR-V7+. Enzalutamide conditioning in some PAC models induced AR-V7+ staining dependent on duration of treatment and AR status of the parent model. Castration status and mouse strain affected enzalutamide activity in some PAC models, including reduced activity in ST1273/CX mice versus intact male nudes. ST4420 tested in CB-17 SCIDs was more sensitive to treatment than in nudes. Conclusion: We have established and characterized a panel of PAC and PNEC XPDX models in SCID and nude strains focusing on AR-V7, AR and PSMA staining and differential enzalutamide activity based on protein staining, mouse strain and castration status. We also reported induction of AR-V7 expression by chronic enzalutamide administration. These models can be utilized as a valuable tool in better understanding castrate-resistant prostate cancer and in developing novel therapies for enzalutamide-resistant patients. Citation Format: Jim Lund, Johnnie Flores, Alyssa Simonson, Armand Diaz III, Jared Knol, Naveen Kella, Drew Rasco, Kyriakos P Papadopoulos, Mark Campbell, Michael J Wick. Establishment and characterization of a panel of prostate cancer XPDX models with differential AR-V7 staining and enzalutamide response [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A080.