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

Abstract

BackgroundProstate-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.MethodsMice 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.ResultsTumor 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.ConclusionARB-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. However, while pre-treatment with ARB increased DNA damage significantly, it did not result in synergistic effects when combined with RLT.Electronic supplementary materialThe online version of this article (10.1186/s13550-018-0451-z) contains supplementary material, which is available to authorized users.

TheraP: a randomized phase 2 trial of 177Lu‐PSMA‐617 theranostic treatment vs cabazitaxel in progressive metastatic castration‐resistant prostate cancer (Clinical Trial Protocol ANZUP 1603)

“…Additionally, there was careful consideration of whether or not eligible patients should have progressed on the new‐generation hormone therapies, such as enzalutamide and abiraterone. While there are studies to suggest that there may be a synergistic effect of 177 Lu‐PSMA‐617 therapy with the new‐generation hormonal therapies , this has only been reported in an in vitro and murine model , with anecdotal human data on the efficacy and tolerability of the combination. Thus, for the present study, we felt it was important to establish the comparative activity of the single agent 177 Lu‐PSMA‐617 first, before pursuing other hypotheses of interest.…”

“…Demonstration of high uptake on 68 Ga‐PSMA‐PET is used for selection of patients for 177 Lu‐PSMA therapy. A number of retrospective studies with substantial variability in treatment regimens have demonstrated favourable PSA responses of >50% in 31–72% of heavily pre‐treated patients with mCRPC .…”

Concentration‐dependent effects of dutasteride on prostate‐specific membrane antigen (PSMA) expression and uptake of 177Lu‐PSMA‐617 in LNCaP cells

“…These results led to a first promising patient report of PSMA upregulation detected by 68 Ga‐PSMA‐11 PET/MRI following 4 weeks of treatment with bicalutamide and a single injection of leuprolide acetate . On the other hand, recently published in vivo data did not show a synergistic treatment effect by using enzalutamide as pretreatment of PSMA‐directed radioligand therapy . Therefore, further research is required to better understand whether short‐term exposure to androgen deprivation therapy might be useful to enhance imaging quality or therapy effects in prostate cancer.…”

“…10 On the other hand, recently published in vivo data did not show a synergistic treatment effect by using enzalutamide as pretreatment of PSMAdirected radioligand therapy. 8 Therefore, further research is required to better understand whether short-term exposure to androgen deprivation therapy might be useful to enhance imaging quality or therapy effects in prostate cancer. However, first (bicalutamide) or second (abiraterone, enzalutamide) generation androgen deprivation therapy is associated with relevant side effects in patients.…”

“…Recent studies demonstrated an increased PSMA expression following treatment with bicalutamide, abiraterone, and enzalutamide in vitro and in vivo. [7][8][9] In addition, results of a first-in-human application have shown a seven-fold increase in PSMA radioligand uptake following treatment with bicalutamide and a single injection of leuprolide acetate. 10 Furthermore, studies suggested a time-dependent effect of androgen receptor (AR) inhibition using enzalutamide on PSMA expression.…”