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Title: Preclinical evaluation of PSMA expression in response to androgen receptor blockade for theranostics in prostate cancer

Abstract

Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) is a promising yet not curative approach in castration-resistant (CR) prostate cancer (PC). Rational combination therapies may improve treatment efficacy. Here, we explored the effect of androgen receptor blockade (ARB) on PSMA expression visualized by PET and its potential additive effect when combined with 177Lu-PSMA RLT in a mouse model of prostate cancer. Mice bearing human CRPC (C4-2 cells) xenografts were treated with 10 mg/kg enzalutamide (ENZ), with 50 mg/kg bicalutamide (BIC), or vehicle (control) for 21 days. PSMA expression was evaluated by 68Ga-PSMA11 PET/CT and quantified by flow cytometry of tumor fine needle aspirations before treatment and on days 23, 29, 34, and 39 post-therapy induction. For the RLT combination approach, mice bearing C4-2 tumors were treated with 10 mg/kg ENZ or vehicle for 21 days before receiving either 15 MBq (84 GBq/μmol) 177Lu-PSMA617 or vehicle. DNA damage was assessed as phospho-γH2A.X foci in tumor biopsies. Reduction of tumor volume on CT and survival were used as study endpoints. Tumor growth was delayed by ARB while 68Ga-PSMA11 uptake increased up to 2.3-fold over time when compared to controls. ABR-induced upregulation of PSMA expression was confirmed by flow cytometry. Phospho-γH2A.X levels increased 1.8-more » and 3.4-fold at 48 h in response to single treatment ENZ or RLT and ENZ+RLT, respectively. Despite significantly greater DNA damage and persistent increase of PSMA expression at the time of RLT, no additional tumor growth retardation was observed in the ENZ+RLT group (vs. RLT only, p = 0.372 at day 81). Median survival did not improve significantly when ENZ was combined with RLT. ARB-mediated increases in PSMA expression in PC xenografts were evident by 68Ga-PSMA11 PET imaging and flow cytometry. 177Lu-PSMA617 effectively decreased C4-2 tumor size. Furthermore, while pre-treatment with ARB increased DNA damage significantly, it did not result in synergistic effects when combined with RLT.« less

Authors:
ORCiD logo [1];  [2];  [3];  [4];  [2];  [2];  [2];  [2];  [2];  [2];  [5];  [2];  [2];  [6]
  1. David Geffen School of Medicine at UCLA, Los Angeles, CA (United States); Univ. of California, Los Angeles, CA (United States)
  2. David Geffen School of Medicine at UCLA, Los Angeles, CA (United States)
  3. Univ. Essen, Essen (Germany)
  4. Lund Univ., Lund (Sweden)
  5. David Geffen School of Medicine at UCLA, Los Angeles, CA (United States); Univ. Essen, Essen (Germany)
  6. Technical Univ. of Munich, Munich (Germany)
Publication Date:
Research Org.:
Univ. of California, Los Angeles, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23). Biological Systems Science Division
OSTI Identifier:
1483931
Grant/Contract Number:  
SC0012353
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
EJNMMI Research
Additional Journal Information:
Journal Volume: 8; Journal Issue: 1; Journal ID: ISSN 2191-219X
Publisher:
Springer Open
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; PSMA; Prostate cancer; 68Ga-PSMA PET/CT; Androgen receptor blockade; Radioligand therapy

Citation Formats

Lückerath, Katharina, Wei, Liu, Fendler, Wolfgang P., Evans-Axelsson, Susan, Stuparu, Andreea D., Slavik, Roger, Mona, Christine E., Calais, Jeremie, Rettig, Matthew, Reiter, Robert E., Herrmann, Ken, Radu, Caius G., Czernin, Johannes, and Eiber, Matthias. Preclinical evaluation of PSMA expression in response to androgen receptor blockade for theranostics in prostate cancer. United States: N. p., 2018. Web. doi:10.1186/s13550-018-0451-z.
Lückerath, Katharina, Wei, Liu, Fendler, Wolfgang P., Evans-Axelsson, Susan, Stuparu, Andreea D., Slavik, Roger, Mona, Christine E., Calais, Jeremie, Rettig, Matthew, Reiter, Robert E., Herrmann, Ken, Radu, Caius G., Czernin, Johannes, & Eiber, Matthias. Preclinical evaluation of PSMA expression in response to androgen receptor blockade for theranostics in prostate cancer. United States. doi:10.1186/s13550-018-0451-z.
Lückerath, Katharina, Wei, Liu, Fendler, Wolfgang P., Evans-Axelsson, Susan, Stuparu, Andreea D., Slavik, Roger, Mona, Christine E., Calais, Jeremie, Rettig, Matthew, Reiter, Robert E., Herrmann, Ken, Radu, Caius G., Czernin, Johannes, and Eiber, Matthias. Mon . "Preclinical evaluation of PSMA expression in response to androgen receptor blockade for theranostics in prostate cancer". United States. doi:10.1186/s13550-018-0451-z. https://www.osti.gov/servlets/purl/1483931.
@article{osti_1483931,
title = {Preclinical evaluation of PSMA expression in response to androgen receptor blockade for theranostics in prostate cancer},
author = {Lückerath, Katharina and Wei, Liu and Fendler, Wolfgang P. and Evans-Axelsson, Susan and Stuparu, Andreea D. and Slavik, Roger and Mona, Christine E. and Calais, Jeremie and Rettig, Matthew and Reiter, Robert E. and Herrmann, Ken and Radu, Caius G. and Czernin, Johannes and Eiber, Matthias},
abstractNote = {Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) is a promising yet not curative approach in castration-resistant (CR) prostate cancer (PC). Rational combination therapies may improve treatment efficacy. Here, we explored the effect of androgen receptor blockade (ARB) on PSMA expression visualized by PET and its potential additive effect when combined with 177Lu-PSMA RLT in a mouse model of prostate cancer. Mice bearing human CRPC (C4-2 cells) xenografts were treated with 10 mg/kg enzalutamide (ENZ), with 50 mg/kg bicalutamide (BIC), or vehicle (control) for 21 days. PSMA expression was evaluated by 68Ga-PSMA11 PET/CT and quantified by flow cytometry of tumor fine needle aspirations before treatment and on days 23, 29, 34, and 39 post-therapy induction. For the RLT combination approach, mice bearing C4-2 tumors were treated with 10 mg/kg ENZ or vehicle for 21 days before receiving either 15 MBq (84 GBq/μmol) 177Lu-PSMA617 or vehicle. DNA damage was assessed as phospho-γH2A.X foci in tumor biopsies. Reduction of tumor volume on CT and survival were used as study endpoints. Tumor growth was delayed by ARB while 68Ga-PSMA11 uptake increased up to 2.3-fold over time when compared to controls. ABR-induced upregulation of PSMA expression was confirmed by flow cytometry. Phospho-γH2A.X levels increased 1.8- and 3.4-fold at 48 h in response to single treatment ENZ or RLT and ENZ+RLT, respectively. Despite significantly greater DNA damage and persistent increase of PSMA expression at the time of RLT, no additional tumor growth retardation was observed in the ENZ+RLT group (vs. RLT only, p = 0.372 at day 81). Median survival did not improve significantly when ENZ was combined with RLT. ARB-mediated increases in PSMA expression in PC xenografts were evident by 68Ga-PSMA11 PET imaging and flow cytometry. 177Lu-PSMA617 effectively decreased C4-2 tumor size. Furthermore, while pre-treatment with ARB increased DNA damage significantly, it did not result in synergistic effects when combined with RLT.},
doi = {10.1186/s13550-018-0451-z},
journal = {EJNMMI Research},
issn = {2191-219X},
number = 1,
volume = 8,
place = {United States},
year = {2018},
month = {10}
}

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