New insights in the paradigm of upregulation of tumoral PSMA expression by androgen receptor blockade: Enzalutamide induces PSMA upregulation in castration-resistant prostate cancer even in patients having previously progressed on enzalutamide

Rosar, Florian; Dewes, Sebastian; Ries, M.; Schaefer, A.; Khreish, Fadi; Maus, Stephan; Bohnenberger, H; Linxweiler, Johannes; Bartholomä, Mark; Ohlmann, Carsten; Ezziddin, Samer

doi:10.1007/s00259-019-04674-0

Cited by 40 publications

(38 citation statements)

References 33 publications

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“…The studies presented here were conducted in immunocompromised mice and additional contribution of the immune system to the antitumor efficacy remains to be elucidated. tracer uptake in CRPC and that the increase in PSMA expression was even seen in patients with previous enzalutamide treatment failure (45). In line with this, we observed enhanced antitumor activity for the combination treatment with PSMA-TTC and darolutamide in the KUCaP-1 prostate cancer PDX model that has previously been shown to be resistant to enzalutamide therapy (29).…”

Section: Discussionsupporting

confidence: 84%

“…(26)(27)(28) and that increased tumor PSMA expression results in higher tumor uptake of PSMA-targeting drugs (40). Furthermore, increased uptake of PSMA-binding positron emission tomography (PET) tracers upon androgen inhibition has been demonstrated in both preclinical prostate cancer models as well as in patients with prostate cancer (40)(41)(42)(43)(44)(45). However, to our knowledge, our data demonstrates for the first time that increased PSMA expression by androgen receptor inhibition can increase the antitumor activity of a radionuclide therapy in a preclinical model of prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

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Darolutamide Potentiates the Antitumor Efficacy of a PSMA-targeted Thorium-227 Conjugate by a Dual Mode of Action in Prostate Cancer Models

Hammer¹,

Schlicker²,

Zitzmann-Kolbe³

et al. 2021

Clinical Cancer Research

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Most patients with prostate cancer undergoing antiandrogen treatment will develop resistance, and thus, novel effective treatments are needed. Here, we explore the combination of the antibody-based targeted alpha therapy PSMA-TTC and the androgen receptor inhibitor darolutamide in preclinical prostate cancer models. This combination is well-tolerated and exhibits synergistic antitumor efficacy. We demonstrate a dual mode-ofaction for this combination treatment, where androgen inhibition (1) induces PSMA expression, resulting in increased PSMA-TTC tumor uptake and enhanced efficacy in a model with low baseline PSMA expression, and (2) prevents the expression of DNA repair pathway genes, leading to increased DNA damage and antitumor efficacy in combination with PSMA-TTC in a model with high baseline PSMA expression. Altogether, our preclinical data suggest that PSMA-TTC and darolutamide combination therapy may be a highly effective treatment option for prostate cancer and support the clinical development of PSMA-TTC in combination with androgen receptor inhibitors, such as darolutamide.Research.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Darolutamide Potentiates the Antitumor Efficacy of a PSMA-targeted Thorium-227 Conjugate by a Dual Mode of Action in Prostate Cancer Models

Hammer¹,

Schlicker²,

Zitzmann-Kolbe³

et al. 2021

Clinical Cancer Research

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“…Radionuclide therapies targeting PSMA have shown some successes in disease management. However, resistance to PSMAtargeted therapies might develop due to (therapy-induced) AR (re) activation (29) and subsequent loss of PSMA expression (30)(31)(32)(33). Furthermore, alpha-particle therapies targeting PSMA are often hindered by dose-limiting toxicities (see below; ref.…”

Section: Discussionmentioning

confidence: 99%

PSA-Targeted Alpha-, Beta-, and Positron-Emitting Immunotheranostics in Murine Prostate Cancer Models and Nonhuman Primates

Veach

Storey

Lückerath

et al. 2021

Clinical Cancer Research

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Purpose: Most patients with prostate cancer treated with androgen receptor (AR) signaling inhibitors develop therapeutic resistance due to restoration of AR functionality. Thus, there is a critical need for novel treatment approaches. Here we investigate the theranostic potential of hu5A10, a humanized mAb specifically targeting free PSA (KLK3).Experimental Design: LNCaP-AR (LNCaP with overexpression of wildtype AR) xenografts (NSG mice) and KLK3_Hi-Myc transgenic mice were imaged with 89 Zr-or treated with 90 Y-or 225 Ac-labeled hu5A10; biodistribution and subcellular localization were analyzed by gamma counting, PET, autoradiography, and microscopy. Therapeutic efficacy of [ 225 Ac]hu5A10 and [ 90 Y]hu5A10 in LNCaP-AR tumors was assessed by tumor volume measurements, time to nadir (TTN), time to progression (TTP), and survival. Pharmacokinetics of [ 89 Zr]hu5A10 in nonhuman primates (NHP) were determined using PET. Results: Biodistribution of radiolabeled hu5A10 constructs was comparable in different mouse models. Specific tumor uptake increased over time and correlated with PSA expression. Treatment with [ 90 Y]/[ 225 Ac]hu5A10 effectively reduced tumor burden and prolonged survival (P ≤ 0.0054). Effects of [ 90 Y]hu5A10 were more immediate than [ 225 Ac]hu5A10 (TTN, P < 0.0001) but less sustained (TTP, P < 0.0001). Complete responses were observed in 7 of 18 [ 225 Ac]hu5A10 and 1 of 9 mice [ 90 Y]hu5A10. Pharmacokinetics of [ 89 Zr]hu5A10 were consistent between NHPs and comparable with those in mice. [ 89 Zr]hu5A10-PET visualized the NHP-prostate over the 2-week observation period.Conclusions: We present a complete preclinical evaluation of radiolabeled hu5A10 in mouse prostate cancer models and NHPs, and establish hu5A10 as a new theranostic agent that allows highly specific and effective downstream targeting of AR in PSAexpressing tissue. Our data support the clinical translation of radiolabeled hu5A10 for treating prostate cancer.

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“…(without any significant change in PSA levels) after a short pre-treatment course of enzalutamide (55). Interestingly, 7 of the 10 patients included in this analysis had previously progressed on enzalutamide.…”

mentioning

confidence: 90%

Prostate-specific membrane antigen (PSMA)-based imaging in localized and advanced prostate cancer: a narrative review

Kouchkovsky¹,

Aggarwal²,

Hope³

2021

Transl Androl Urol

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Combined molecular and morphologic imaging modalities have emerged in recent years as an alternative to conventional imaging in prostate cancer (PC). In particular, novel prostate-specific membrane antigen (PSMA) radiotracers have demonstrated increased sensitivity and specificity for the initial staging of men with clinically localized PC, as well as for PC detection in the setting of biochemical recurrence (BCR).Molecular imaging is increasingly used to guide treatment decisions in these patients-though its impact on survival has yet to be established. Improved PC detection in men with BCR has also helped to identify a subset of patients with oligometastatic disease. The optimal management of oligometastatic PC and the role of metastasis-directed therapies (MDT) are the subjects of ongoing studies. In comparison to clinically localized or biochemically recurrent PC, the role of molecular imaging in men with advanced disease is less established. In metastatic castration-resistant PC (mCRPC), PSMA-based imaging has primarily been investigated as a companion diagnostic tool to predict and monitor response to PSMA-targeted radioligand therapy (RLT). More recent efforts have focused on using molecular imaging to monitor treatment response to conventional chemohormonal therapies. However, despite promising early results, several barriers remain to the widespread use of PSMA-based imaging in metastatic PC: temporary flares in PSMA uptake have been described in a subset of patients after initiation of therapy, and the underlying mechanism and clinical implications of this phenomenon are still poorly understood. Furthermore, whereas PSMA is invariably expressed in hormone-sensitive PC, loss of PSMA expression is increasingly recognized in a subset of mCRPC patients with aggressive disease. Although this may limit the use of PSMA-based imaging as a standalone modality in advanced PC, loss of PSMA uptake may also provide non-invasive and clinically relevant molecular insight on patients' underlying tumor biology.

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New insights in the paradigm of upregulation of tumoral PSMA expression by androgen receptor blockade: Enzalutamide induces PSMA upregulation in castration-resistant prostate cancer even in patients having previously progressed on enzalutamide

Cited by 40 publications

References 33 publications

Darolutamide Potentiates the Antitumor Efficacy of a PSMA-targeted Thorium-227 Conjugate by a Dual Mode of Action in Prostate Cancer Models

Darolutamide Potentiates the Antitumor Efficacy of a PSMA-targeted Thorium-227 Conjugate by a Dual Mode of Action in Prostate Cancer Models

PSA-Targeted Alpha-, Beta-, and Positron-Emitting Immunotheranostics in Murine Prostate Cancer Models and Nonhuman Primates

Prostate-specific membrane antigen (PSMA)-based imaging in localized and advanced prostate cancer: a narrative review

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