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Updated: Jan 5, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Galeterone and The Next Generation Galeterone Analogs, VNPP414 and VNPP433-3β Exert Potent Therapeutic Effects in
Andrew K Kwegyir-Afful1,2, Senthilmurugan Ramalingam3,4, Vidya P Ramamurthy5,6
1Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. Andrew.kwegyir-Afful@fda.hhs.gov.
Abstract:
These studies compared the efficacies of our clinical agent galeterone (Gal) and the FDA-approved prostate cancer drug, enzalutamide (ENZ) with two lead next generation galeterone analogs (NGGAs), VNPP414 and VNPP433-3β, using prostate cancer (PC) in vitro and in vivo models. Antitumor activities of orally administered agents were also assessed in CWR22Rv1 tumor-bearing mice. We demonstrated that Gal and NGGAs degraded AR/AR-V7 and Mnk1/2; blocked cell cycle progression and proliferation of human PC cells; induced apoptosis; inhibited cell migration, invasion, and putative stem cell markers; and reversed the expression of epithelial-to-mesenchymal transition (EMT). In addition, Gal/NGGAs (alone or in combination) also inhibited the growth of ENZ-, docetaxel-, and mitoxantrone-resistant human PC cell lines. The NGGAs exhibited improved pharmacokinetic profiles over Gal in mice. Importantly, in vivo testing showed that VNPP433-3β (at 7.53-fold lower equimolar dose than Gal) markedly suppressed (84% vs. Gal, 47%; p < 0.01) the growth of castration-resistant PC (CRPC) CWR22Rv1 xenograft tumors, with no apparent host toxicity. ENZ was ineffective in this CRPC xenograft model. In summary, our findings show that targeting AR/AR-V7 and Mnk1/2 for degradation represents an effective therapeutic strategy for PC/CRPC treatment and supports further development of VNPP433-3β towards clinical investigation.
Insights
New galeterone analogs (NGGAs) show potent anti-prostate cancer activity by degrading AR/AR-V7 and Mnk1/2. VNPP433-3β demonstrated significant tumor suppression in vivo with minimal toxicity, outperforming enzalutamide.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Prostate cancer (PC) remains a significant health challenge, with resistance to current therapies like enzalutamide (ENZ) being a major concern.
- Androgen receptor (AR) signaling and its splice variants (AR-V7) are key drivers of PC progression.
- The Mnk1/2 pathway is implicated in cancer cell proliferation and survival.
Purpose of the Study:
- To compare the efficacy of galeterone (Gal) and enzalutamide (ENZ) with novel next-generation galeterone analogs (NGGAs) in preclinical prostate cancer models.
- To evaluate the antitumor activity and pharmacokinetic profiles of NGGAs.
- To investigate the therapeutic potential of targeting AR/AR-V7 and Mnk1/2 in prostate cancer.
Main Methods:
- In vitro and in vivo studies using prostate cancer cell lines and xenograft models (CWR22Rv1).
- Assessment of antitumor activity, including cell cycle progression, apoptosis, migration, invasion, and stem cell markers.
- Pharmacokinetic profiling of Gal and NGGAs in mice.
- Evaluation of drug resistance mechanisms.
Main Results:
- Gal and NGGAs degraded AR/AR-V7 and Mnk1/2, inhibiting PC cell proliferation and inducing apoptosis.
- NGGAs reversed epithelial-to-mesenchymal transition (EMT) and inhibited stem cell markers.
- Gal/NGGAs demonstrated efficacy against enzalutamide-, docetaxel-, and mitoxantrone-resistant cell lines.
- VNPP433-3β showed superior in vivo efficacy in castration-resistant PC xenografts compared to Gal, with no observed toxicity.
- Enzalutamide was ineffective in the castration-resistant PC xenograft model.
Conclusions:
- Targeting AR/AR-V7 and Mnk1/2 for degradation is a viable therapeutic strategy for prostate cancer, including castration-resistant forms.
- NGGAs, particularly VNPP433-3β, exhibit promising preclinical efficacy and improved pharmacokinetic profiles.
- VNPP433-3β warrants further clinical development for prostate cancer treatment.
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