Preclinical evaluation of PSMA expression in response to androgen receptor blockade for theranostics in prostate cancer [electronic resource]

• Ngôn ngữ: eng
• Ký hiệu phân loại: 616.99 Tumors and miscellaneous communicable diseases
• Thông tin xuất bản: Washington, D.C. : Oak Ridge, Tenn. : United States. Dept. of Energy. Office of Science ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2018
• Mô tả vật lý: Size: 9 p. : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 260146
• Chủ đề: 1. 60 applied life sciences; 2. 68ga-psma petct; 3. Androgen receptor blockade; 4. Prostate cancer; 5. Psma; 6. Radioligand therapy

Tóm tắt

 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 <
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 Lu-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 <
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 Ga-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/?mol) <
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 Lu-PSMA617 or vehicle. DNA damage was assessed as phospho-?H2A.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 <
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 Ga-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-?H2A.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, <
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  = 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 <
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 Ga-PSMA11 PET imaging and flow cytometry. <
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 Lu-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.