Synergistic co‐targeting of prostate‐specific membrane antigen and androgen receptor in prostate cancer

Murga, Jose D.; Moorji, Sameer M.; Han, Amy; Magargal, Wells W.; DiPippo, Vincent A.; Olson, William C.

doi:10.1002/pros.22910

Cited by 78 publications

(144 citation statements)

References 49 publications

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“…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. Further investigations suggested a time‐dependent effect of AR inhibition using enzalutamide on PSMA expression in vitro . Later, Evans et al showed that enzalutamide increases PSMA expression also in vivo and that these changes can be quantitatively measured by using PET imaging.…”

Section: Discussionmentioning

confidence: 99%

“…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 . Furthermore, studies suggested a time‐dependent effect of androgen receptor (AR) inhibition using enzalutamide on PSMA expression . Our group has previously demonstrated that PSMA expression can also be upregulated using high concentrations of dutasteride in vitro .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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Background Prostate‐specific membrane antigen (PSMA)‐based imaging and therapy are increasingly used in the management of prostate cancer. However, low PSMA surface expression in certain patients is a limitation for PSMA‐based technologies. We have previously shown that high doses of dutasteride, a 5α‐reductase inhibitor generally used for the treatment of benign prostatic enlargement, increase the PSMA expression in vitro. We now further analyzed the concentration‐ and time‐dependent effects of dutasteride in LNCaP cells. Methods Androgen receptor (AR) expressing prostate cancer cells (LNCaP) were treated for 7 to 14 days with vehicle control (0.1% dimethyl sulfoxide) or different concentrations of dutasteride (0.25 , 0.5 , 1 , and 5 μM). In addition to cell proliferation, PSMA surface expression was assessed using flow cytometry (FACS) and immunocytochemistry. Total PSMA and AR expression was analyzed by capillary western immunoassay (WES). In addition, tumor cell uptake and internalization assays of 177Lu‐PSMA‐617 were performed. Results Dutasteride treatment resulted in a significant upregulation of PSMA surface expression compared to vehicle control after 7 days in all tested concentrations. After 14 days a further, concentration‐dependent increase of PSMA surface expression was detectable. Total PSMA protein expression significantly increased after treatment of cells with high concentrations of dutasteride using 5 μM for 7 or 14 days. However, when lower concentrations were used total PSMA expression was not significantly altered compared to vehicle control. Further testing revealed a dose‐dependent increase in uptake and internalization of 177Lu‐PSMA‐617 after 7 and 14 days. Though, a significantly increased uptake was only observed using a 5 μM dutasteride concentration for 7 days as well as 1 and 5 μM for 14 days. Conclusion Our investigations revealed a concentration‐ and time‐dependent effect of dutasteride on PSMA expression and uptake of 177Lu‐PSMA‐617 in LNCaP cells. A short‐term treatment of patients with high doses of dutasteride might increase the detection rate of PSMA‐based imaging and increase the effect of 177Lu‐PSMA‐617 therapy via upregulation of PSMA expression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…PSMA, also known as folate hydrolase 1, hydrolyzes polyglutamated folates and additionally functions as a folate transporter. PSMA overexpression stimulates both folate transport and prostate cancer cell proliferation . We hypothesize that 5‐FU, binding to TS or by metabolite incorporation into RNA or DNA , may have preferential effects as a consequence of increased PSMA expression.…”

Section: Resultsmentioning

confidence: 98%

Extreme Prostate-Specific Antigen Response to Infusional 5-Flourouracil in Castrate-Resistant Prostate Cancer

et al. 2017

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Prostate cancer that has progressed after androgen deprivation, abiraterone, and taxane therapy is challenging to treat successfully. Herein we report a dramatic response to continuous-infusion 5-fluorouracil (5-FU) at a dose of 200 mg/m in a patient with rapidly progressive, heavily pretreated, metastatic castrate-resistant prostate cancer. Baseline prostate-specific antigen values declined from 1,890 ng/mL to <1 ng/mL after 5-FU therapy. We hypothesized that prostate-specific membrane antigen overexpression may result in cancer cells uniquely susceptible to antifolate therapies.

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“…Newer agents are continued to be tested, including an ongoing phase I study of EC1169, a PSMA-targeting moiety linked to tubulysin B hydrazide, which have shown highly favorable toxicity profile to date (NCT02202447). 40 Both in vitro 41,42 and mice model 43 studies have shown synergisms between PSMA ADC and newly available agents such abiraterone, enzalutamide, and rapamycin, offering a wealth of combination, which have not been evaluated in human studies. As PSMA is highly restricted to prostatic tissue, it has also been actively investigated as a target for therapeutic vaccine and immunotherapy, which is being covered in detail in a different article elsewhere in this issue.…”

Section: Psma-directed Chemotherapymentioning

confidence: 99%

Prostate-Specific Membrane Antigen–Directed Therapy for Metastatic Castration-Resistant Prostate Cancer

Teo

Morris²

2016

The Cancer Journal

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Prostate-specific membrane antigen (PSMA) is highly expressed on both benign and malignant prostatic tissue. Prostate-specific membrane antigen–directed therapy is conceptually promising, with a potential to additionally serve as a theranostic model in management of advanced prostate cancer. To date, various approaches have been devised and tested, including radiolabeled PSMA antibodies and inhibitor and antibody-drug conjugates. However, development and progress have faced challenges in determining the optimal combination of payload, PSMA-binding moiety, and linker technology. We review the available clinical data to date in PSMA-directed therapies and discuss the challenges faced.

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Synergistic co‐targeting of prostate‐specific membrane antigen and androgen receptor in prostate cancer

Abstract: The findings support exploration of clinical treatment regimens that combine potent antiandrogens and PSMA-targeted therapies for prostate cancer.

Cited by 78 publications

References 49 publications

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

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

Extreme Prostate-Specific Antigen Response to Infusional 5-Flourouracil in Castrate-Resistant Prostate Cancer

Prostate-Specific Membrane Antigen–Directed Therapy for Metastatic Castration-Resistant Prostate Cancer

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Synergistic co‐targeting of prostate‐specific membrane antigen and androgen receptor in prostate cancer

Abstract: The findings support exploration of clinical treatment regimens that combine potent antiandrogens and PSMA-targeted therapies for prostate cancer.

Cited by 78 publications

References 49 publications

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

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

Extreme Prostate-Specific Antigen Response to Infusional 5-Flourouracil in Castrate-Resistant Prostate Cancer

Prostate-Specific Membrane Antigen–Directed Therapy for Metastatic Castration-Resistant Prostate Cancer

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Product

Resources

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

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