Dietary Tomato, but Not Lycopene Supplementation, Impacts Molecular Outcomes of Castration-resistant Prostate Cancer in the TRAMP Model (P05-015-19)

Abstract Objectives The objective was to determine whether dietary tomato or lycopene supplementation impacted the expression of biomarkers associated with aggressive tumors and poorer prognostic outcomes in castration-resistant prostate cancer (CRPC). Methods Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were castrated at 12 weeks of age to mimic the effects of androgen deprivation therapy (ADT) leading to CRPC. Mice were separated into three dietary groups (n = 30/group) and fed powdered, modified AIN-93 G diets containing 10% tomato powder (TP), lycopene beadlets matched for lycopene content of TP (LYCO), or placebo beadlets (PLAC). Tumors were detected and monitored for growth by ultrasound scan. After 5 weeks of CRPC growth, mice were euthanized, and prostate and tumor tissues were collected. Histological analysis was used to identify presence of tumor neuroendocrine (NE) phenotype (by synaptophysin [syp] expression) and androgen receptor (AR) expression. ELISA and Western blot were used to quantify interleukin-6 (IL-6) and STAT3, and RT-PCR was used to measure downstream targets of both AR and STAT3. Results No differences were observed between AR expression or presence of the NE phenotype between dietary groups. However, lower tumor weight was associated with both AR and syp expression in mice fed TP. A positive correlation (P = 0.03) was observed between reduced tumor IL-6 (P = 0.012) and reduced phosphorylation (activation) of STAT3 (P = 0.017) in tumors of mice fed TP when compared to PLAC or LYCO. RNA analysis showed reduced expression of genes related to invasion (mmp-2; P = 0.006), cell proliferation (cdk1; P = 0.01), NE phenotype (ngfr; P = 0.001), and androgen metabolism (srd5a2; P = 0.03) in tumors of TP-fed mice. Conclusions Physiological levels of dietary tomato, but not lycopene supplementation, reduced the expression of molecular biomarkers typically upregulated in CRPC tissues that are associated with tumor growth and metastasis. Funding Sources This research is supported by the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health.

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Dietary Tomato or Lycopene Do Not Reduce Castration-Resistant Prostate Cancer Progression in a Murine Model

Journal of Nutrition ◽

10.1093/jn/nxaa107 ◽

2020 ◽

Vol 150 (7) ◽

pp. 1808-1817

Author(s):

Joe L Rowles ◽

Joshua W Smith ◽

Catherine C Applegate ◽

Rita J Miller ◽

Matthew A Wallig ◽

...

Keyword(s):

Prostate Cancer ◽

De Novo ◽

Control Diet ◽

Tumor Detection ◽

Castration Resistant Prostate Cancer ◽

Tumor Weight ◽

Castration Resistant ◽

Mouse Prostate ◽

Tomato Powder ◽

Tramp Mice

ABSTRACT Background Dietary tomato products or lycopene protect against prostate carcinogenesis, but their impact on the emergence of castration-resistant prostate cancer (CRPC) is unknown. Objective We hypothesized that tomato or lycopene products would reduce the emergence of CRPC. Methods Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were castrated at 12–13 wk and the emergence of CRPC was monitored by ultrasound in each study. In Study 1, TRAMP mice (n = 80) were weaned onto an AIN-93G-based control diet (Con-L, n = 28), a 10% tomato powder diet (TP-L, 10% lyophilized w/w, n = 26), or a control diet followed by a tomato powder diet after castration (TP-Int1, n = 26). In Study 2, TRAMP mice (n = 85) were randomized onto a control diet with placebo beadlets (Con-Int, n = 29), a tomato diet with placebo beadlets (TP-Int2, n = 29), or a control diet with lycopene beadlets (Lyc-Int, n = 27) following castration (aged 12 wk). Tumor incidence and growth were monitored by ultrasound beginning at an age of 10 wk. Mice were euthanized 4 wk after tumor detection or aged 30 wk if no tumor was detected. Tissue weights were compared by ANOVA followed by Dunnett's test. Tumor volumes were compared using generalized linear mixed model regression. Results Ultrasound estimates for the in vivo tumor volume were strongly correlated with tumor weight at necropsy (R2 = 0.75 and 0.94, P <0.001 for both Studies 1 and 2, respectively). Dietary treatments after castration did not significantly impact cancer incidence, time to tumor detection, or final tumor weight. Conclusions In contrast to studies of de novo carcinogenesis in multiple preclinical models, tomato components had no significant impact on the emergence of CRPC in the TRAMP model. It is possible that specific mutant subclones of prostate cancer may continue to show some antiproliferative response to tomato components, but further studies are needed to confirm this.

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Single-lesion PSMA protein expression and response to Lu-177 PSMA therapy in patients with castration-resistant prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.5065 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 5065-5065

Author(s):

Judith Stangl-Kremser ◽

Sazan Rasul ◽

Jeffrey J. Tosoian ◽

Simpa Salami ◽

Alexander Zaslavsky ◽

...

Keyword(s):

Prostate Cancer ◽

Protein Expression ◽

Pet Imaging ◽

Metastatic Tumor ◽

Specific Response ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Tumor Tissues ◽

Psma Pet ◽

Psma Expression

5065 Background: The recent introduction of Lu-177 PSMA for the treatment of castration-resistant prostate cancer (CRPC) has been met with much excitement. Initial reports of clinical response are promising, despite known inter- and intra-patient molecular heterogeneity. In this study, we examined the utility of PSMA protein expression in metastatic tumor tissues as a predictor of lesion-specific response to Lu-177 PSMA therapy in men with CRPC. Methods: Between 2015-2020, 19 patients with metastases at multiple sites underwent metastatic lesion biopsy, Ga-68 PSMA PET imaging, and subsequent treatment with three cycles of Lu-177 PSMA. A monoclonal anti-PSMA antibody (EPITOMICS (USA), 1:50) was used to semi-quantitatively assess PSMA protein expression in the biopsy specimen. The histoscore (range 0-300) was derived from intensity and extent of the immunohistochemistry staining and was determined by experienced genitourinary pathologists. Imaging evaluation was performed according to the Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) criteria. We assessed the association of the PSMA protein expression in metastatic tumor tissues and the lesion-specific response to Lu-177 PSMA therapy. Results: In 12 patients with biopsy specimens available for staining, PSMA expression correlated with enhancement (SUVmax) of the biopsy site on Ga-68 PSMA PET imaging (rs = 0.63). Of the nine patients with repeat imaging after Lu-177 PSMA therapy, five (55.6%) had a lesion-specific response at the site of biopsy. PSMA expression on immunohistochemistry was unable to accurately predict lesion-specific response in univariable analysis (p = 0.81, 95% CI 94.6-76.6). Among the five men with a lesion-specific response, three (60%) experienced overall progression based on PERCIST. There was no association between lesion-specific response and overall progression (p = 0.64). Conclusions: In patients with multiple metastases, PSMA protein expression from a single site biopsy was not predictive of site-specific Lu-177 PSMA response based on PERCIST. Additional studies are necessary to further interrogate the clinical consequence of PSMA expression heterogeneity in metastatic sites as well as the mechanisms underpinning resistance to Lu-177 PSMA in patients with CRPC.

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Experimental 177Lu-PSMA-617 radioligand therapy in a patient with extended metastasized leiomyosarcoma

Nuklearmedizin ◽

10.1055/a-0914-2486 ◽

2019 ◽

Vol 58 (04) ◽

pp. 328-330 ◽

Cited By ~ 1

Author(s):

Michael Jüptner ◽

Marlies Marx ◽

Maaz Zuhayra ◽

Ulf Lützen

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Molecular Surface ◽

Castration Resistant Prostate Cancer ◽

Prostate Cancer Cells ◽

Radioligand Therapy ◽

Castration Resistant ◽

Tumor Tissues ◽

Specific Membrane ◽

Psma Expression

IntroductionSystemic radionuclide therapy with 177Lu-PSMA-617 is a novel treatment option in patients with metastasized and castration-resistant prostate cancer 4. The molecular target of the 177Lu-PSMA-617 radioligand therapy is the prostate-specific membrane antigen (PSMA) highly expressed on prostate cancer cells. Beyond the enhanced accumulation of PSMA on prostate cancer cells, PSMA expression is also found on the molecular surface or in the tumor-associated neovasculature of various tumor tissues including sarcomas of the soft tissue 2. Thus, PSMA has theoretically been discussed as a possible future target for systemic radioligand therapy with 177Lu-PSMA-617 even in non-prostate malignancies 1.Here we report on a female patient with extended metastasized leiomyosarcoma experimentally treated with one application of 177Lu-PSMA-617 radioligand therapy.

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