Enzalutamide Enhances PSMA Expression of PSMA-Low Prostate Cancer.

Magdalena Staniszewska,Matthias Eiber,Wolfgang P Fendler,Pedro Fragoso Costa,Katharina Lückerath,Jasmin M Klose,Henning Reis,Tibor Szarvas,Jasmin Wosniack,Boris Hadaschik,Janette Iking,Ken Herrmann

doi:10.3390/ijms22147431

Abstract

Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) prolongs overall survival in men with metastatic castration-resistant prostate cancer (mCRPC). However, men with low PSMA expression are excluded from RLT. We explored the effect of androgen receptor blockade with enzalutamide on PSMA expression. Assessment of PSMA and androgen receptor (AR) expression on the human PC cell lines 22Rv1, C4-2, and LNCaP by immunohistochemistry and flow cytometry revealed low (22Rv1) and high (C4-2 and LNCaP) PSMA expression, and high, comparable AR positivity. Treatment with enzalutamide increased PSMA levels in 22Rv1, C4-2, and LNCaP (2.2/2.3/2.6-fold, p = 0.0005/0.03/0.046) after one week compared to DMSO-treated controls as assessed by flow cytometry. NOD/Scid mice bearing 22Rv1 tumors were treated with enzalutamide for two weeks. Positron emission tomography/computed tomography (PET/CT) demonstrated higher tumor uptake of 68Ga-PSMA after enzalutamide treatment (p = 0.004). Similarly, a clinical case with low baseline PSMA avidity demonstrated increased uptake of 68Ga-PSMA after enzalutamide on PET/CT and post-therapeutic 177Lu-PSMA scintigraphy in a patient with mCRPC. Enzalutamide induced PSMA expression in the 22Rv1 xenograft model and in an mCRPC patient, both with low baseline tumoral PSMA levels. Therefore, enzalutamide pre-treatment might render patients with low PSMA expression eligible for 177Lu-PSMA RLT.

Highlights

Androgen deprivation therapy (ADT) and androgen receptor blockade (ARB) are important components of prostate cancer (PC) management [1]
Patients with Prostate-specific membrane antigen (PSMA)-low PC are not eligible for radioligand therapy (RLT) and might benefit from PSMA enhancing therapy to enable subsequent RLT. While it has been shown in a model of PSMA-high PC that ARB-induced increases in PSMA expression can lead to higher numbers of DNA double-strand breaks following RLT [16], data on the impact of enzalutamide on PSMA levels in PSMA-low PC are lacking so far
Enzalutamide significantly increased PSMA expression levels after one week of treatment in all cell lines compared to vehicle-treated controls

Summary

Introduction

Androgen deprivation therapy (ADT) and androgen receptor blockade (ARB) are important components of prostate cancer (PC) management [1]. Enzalutamide increases median radiographic progression-free (rPFS) survival by. Radioligand therapy (RLT) targeting the prostate-specific membrane antigen (PSMA) is a new therapeutic option for CRPC patients [5,6,7]. Patients with PSMA-low PC are not eligible for RLT and might benefit from PSMA enhancing therapy to enable subsequent RLT. While it has been shown in a model of PSMA-high PC that ARB-induced increases in PSMA expression can lead to higher numbers of DNA double-strand breaks following RLT [16], data on the impact of enzalutamide on PSMA levels in PSMA-low PC are lacking so far. We assess in vitro, in vivo and in an mCRPC clinical case whether enzalutamide treatment can induce PSMA expression in PSMA-low, RLT-ineligible prostate cancer

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Discussion

Conclusion