Influence of Androgen Deprivation Therapy on the Uptake of PSMA-Targeted Agents: Emerging Opportunities and Challenges

Abstract

Prostate-specific membrane antigen (PSMA) is an attractive target for both diagnosis and therapy because of its high expression in the vast majority of prostate cancers. Development of small molecules for targeting PSMA is important for molecular imaging and radionuclide therapy of prostate cancer. Recent evidence implies that androgen-deprivation therapy increase PSMA-ligand uptake in some cases. The reported upregulations in PSMA-ligand uptake after exposure to second-generation antiandrogens such as enzalutamide and abiraterone might disturb PSMA-targeted imaging for staging and response monitoring of patients undergoing treatment with antiandrogen-based drugs. On the other hand, second-generation antiandrogens are emerging as potential endoradio-/chemosensitizers. Therefore, the enhancement of the therapeutic efficiency of PSMA-targeted theranostic methods can be listed as a new capability of antiandrogens. In this manuscript, we will present what is currently known about the mechanism of increasing PSMA uptake following exposure to antiandrogens. In addition, we will discuss whether these above-mentioned antiandrogens could play the role of endoradio-/chemosensitizers in combination with the well-established PSMA-targeted methods for pre-targeting of prostate cancer.

Prospective study on the effect of short-term androgen deprivation therapy on PSMA uptake evaluated with 68Ga-PSMA-11 PET/MRI in men with treatment-naïve prostate cancer

“…It has already been demonstrated that in both androgensensitive and androgen-resistant human prostate adenocarcinoma cells (LNCaP), the expression of PSMA is upregulated post-ADT and downregulated in the presence of testosterone or DHT [14][15][16]. Although a case report published by Hope et al corroborated these preclinical studies, demonstrating a 7fold increase in PSMA SUVmax values after the initiation of ADT, our results are in line with the two very recently published studies [10][11][12].…”

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

“…Recent data suggests that androgen deprivation therapy increases PSMA expression under certain circumstances. 19 Thus, upregulation of PSMA expression following androgen withdrawal has already been described in 1996 by Wright et al 20 In addition, Meller et al 9 revealed an increased PSMA expression following short-term treatment of prostate cancer cells with abiraterone. Further investigations suggested a timedependent effect of AR inhibition using enzalutamide on PSMA expression in vitro.…”

“…In addition, the antitumor activity of 177 Lu‐PSMA‐617 radioligand therapy might be improved after inducing PSMA expression. Recent data suggests that androgen deprivation therapy increases PSMA expression under certain circumstances . Thus, upregulation of PSMA expression following androgen withdrawal has already been described in 1996 by Wright et al In addition, Meller et al revealed an increased PSMA expression following short‐term treatment of prostate cancer cells with abiraterone.…”

Neuroendocrine differentiation of prostate cancer leads to PSMA suppression

“…Clinical reports show the possibility of a false-positive uptake of PSMA-targeted radioligand after ARPI (Hope et al 2017) and a false-negative uptake of this radioligand in NEPC (Chakraborty et al 2015, Tosoian et al 2017, Usmani et al 2017. We previously reviewed the available preclinical evidence justifying molecular backgrounds of a false-positive uptake of PSMA-targeted radioligand after ARPI (Bakht et al 2017). However, there is a lack of preclinical evidence for the reported false-negative uptake of PSMA-targeted radioligand.…”