Galeterone and The Next Generation Galeterone Analogs, VNPP414 and VNPP433-3β Exert Potent Therapeutic Effects in Castration-/Drug-Resistant Prostate Cancer Preclinical Models In Vitro and In Vivo

Andrew K Kwegyir-Afful; Senthilmurugan Ramalingam; Vidya P Ramamurthy; Puranik Purushottamachar; Francis N Murigi; Tadas S Vasaitis; Weiliang Huang; Maureen A Kane; Yuji Zhang; Nicholas Ambulos; Sudhir Tiwari; Pratima Srivastava; Ivo P Nnane; Arif Hussain; Yun Qiu; David J Weber; Vincent C O Njar

doi:10.3390/cancers11111637

Galeterone and The Next Generation Galeterone Analogs, VNPP414 and VNPP433-3β Exert Potent Therapeutic Effects in Castration-/Drug-Resistant Prostate Cancer Preclinical Models In Vitro and In Vivo

Cancers (Basel). 2019 Oct 24;11(11):1637. doi: 10.3390/cancers11111637.

Authors

Andrew K Kwegyir-Afful^{1

2}, Senthilmurugan Ramalingam^{3

4}, Vidya P Ramamurthy^{5

6}, Puranik Purushottamachar^{7

8}, Francis N Murigi^{9

10}, Tadas S Vasaitis¹¹, Weiliang Huang¹², Maureen A Kane¹³, Yuji Zhang^{14

15}, Nicholas Ambulos¹⁶, Sudhir Tiwari¹⁷, Pratima Srivastava¹⁸, Ivo P Nnane¹⁹, Arif Hussain^{20

21}, Yun Qiu^{22

23

24}, David J Weber^{25

26

27}, Vincent C O Njar^{28

29

30}

Affiliations

¹ Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. Andrew.kwegyir-Afful@fda.hhs.gov.
² Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. Andrew.kwegyir-Afful@fda.hhs.gov.
³ Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. SRamalingam@som.umaryland.edu.
⁴ Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. SRamalingam@som.umaryland.edu.
⁵ Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. rv.darsini@gmail.com.
⁶ Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. rv.darsini@gmail.com.
⁷ Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. PPuranik@som.umaryland.edu.
⁸ Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. PPuranik@som.umaryland.edu.
⁹ Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. njamurigi@gmail.com.
¹⁰ Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. njamurigi@gmail.com.
¹¹ Department of Pharmaceutical Sciences, School of Pharmacy and Health Professions, University of Maryland Eastern Shore, 207 Somerset Hall, Princess Anne, MD 21853, USA. tsvasaitis@umes.edu.
¹² Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA. whuang@rx.umaryland.edu.
¹³ Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA. mkane@rx.umaryland.edu.
¹⁴ Division of Biostatistics and Bioinformatics, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA. Yuzhang@som.umaryland.edu.
¹⁵ Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Yuzhang@som.umaryland.edu.
¹⁶ Department of Microbiology and Immunology and University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA. NAmbulos@som.umaryland.edu.
¹⁷ DMPK (Biology Division), GVK BIO, Nacharam, Hyderabad 500076, India. Sudhir.Tiwari@gvkbio.com.
¹⁸ DMPK (Biology Division), GVK BIO, Nacharam, Hyderabad 500076, India. pratima.srivastava@gvkbio.com.
¹⁹ Janssen Research & Development, Spring House, PA 19477, USA. nnanepalle@hotmail.com.
²⁰ Veterans Affairs Medical Center, Baltimore, MD 21201, USA. AHussain@som.umaryland.edu.
²¹ Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. AHussain@som.umaryland.edu.
²² Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. YQiu@som.umaryland.edu.
²³ Veterans Affairs Medical Center, Baltimore, MD 21201, USA. YQiu@som.umaryland.edu.
²⁴ Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. YQiu@som.umaryland.edu.
²⁵ Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. DWeber@som.umaryland.edu.
²⁶ Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. DWeber@som.umaryland.edu.
²⁷ Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. DWeber@som.umaryland.edu.
²⁸ Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. vnjar@som.umaryland.edu.
²⁹ Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. vnjar@som.umaryland.edu.
³⁰ Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. vnjar@som.umaryland.edu.

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.

Keywords: Mnk-eIF4E/mTORC1 signaling pathways; Mnk1/2 degraders; NGGAs; VNPP433-3β AR/AR-V7; apoptosis; castration-/drug-resistant PC cell; galeterone (Gal); prostate cancer.

Abstract

Grants and funding