Predictive value of epithelial‐mesenchymal‐transition (EMT) signature and PARP‐1 in prostate cancer radioresistance

Stark, Timothy; Hensley, Patrick J.; Spear, Amanda; Peng, Hong; Strup, Stephen S.; Kyprianou, Natasha

doi:10.1002/pros.23435

Cited by 34 publications

(27 citation statements)

References 44 publications

(126 reference statements)

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“…This specific adjuvant treatment benefits patients with defective DNA-damage repair such as the BRCA1 and BRCA2 mutations that frequently occur in breast and ovarian cancers [20,21]. Studies involving PARPi for the treatment of PCa are already underway [22,23]. In this context, one strategy for the discovery of new cancer biomarkers and/or potential therapeutic targets is to integrate genomic data from genetically engineered mouse models (GEMMs) and human cancer patients [24,25].…”

Section: Introductionmentioning

confidence: 99%

Sulfiredoxin as a Potential Therapeutic Target for Advanced and Metastatic Prostate Cancer

Barquilha

Santos

Monção

et al. 2020

Oxidative Medicine and Cellular Longevity

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The incidence of prostate cancer (PCa) is increasing, and it is currently the second most frequent cause of death by cancer in men. Despite advancements in cancer therapies, new therapeutic approaches are still needed for treatment-refractory advanced metastatic PCa. Cross-species analysis presents a robust strategy for the discovery of new potential therapeutic targets. This strategy involves the integration of genomic data from genetically engineered mouse models (GEMMs) and human PCa datasets. Considering the role of antioxidant pathways in tumor initiation and progression, we searched oxidative stress-related genes for a potential therapeutic target for PCa. First, we analyzed RNA-sequencing data from Pb-Cre4; Ptenf/f mice and discovered an increase in sulfiredoxin (Srxn1) mRNA expression in high-grade prostatic intraepithelial neoplasia (PIN), well-differentiated adenocarcinoma (medium-stage tumors), and poor-differentiated adenocarcinoma (advanced-stage prostate tumors). The increase of SRXN1 protein expression was confirmed by immunohistochemistry in mouse prostate tumor paraffin samples. Analyses of human databases and prostate tissue microarrays demonstrated that SRXN1 is overexpressed in a subset of high-grade prostate tumors and correlates with aggressive PCa with worse prognosis and decreased survival. Analyses in vitro showed that SRXN1 expression is also higher in most PCa cell lines compared to normal cell lines. Furthermore, siRNA-mediated downregulation of SRXN1 led to decreased viability of PCa cells LNCaP. In conclusion, we identified the antioxidant enzyme SRXN1 as a potential therapeutic target for PCa. Our results suggest that the use of specific SRXN1 inhibitors may be an effective strategy for the adjuvant treatment of castration-resistant PCa with SRXN1 overexpression.

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Section: Introductionmentioning

confidence: 99%

Sulfiredoxin as a Potential Therapeutic Target for Advanced and Metastatic Prostate Cancer

Barquilha

Santos

Monção

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…Actually, it is associated with a younger age of occurrence and is diagnosed as diffuse-type at stage III/IV, showed a significantly higher recurrence rate, higher probability of developing peritoneal seeding at the first site of recurrence, and extremely poor survival compared to other subtypes. Furthermore, it has been reported that PARP-1, which is involved in the mechanism of radiation induced DNA damage repair, is increased in the mesenchymal phenotype, and it could reduce the cell killing effects of RT in prostate cancer [7,8]. In addition, hypoxia, which is a hallmark of tumor and the most important cause of radioresistance, was reported to be associated with the loss of E-cadherin [9].…”

Section: Discussionmentioning

confidence: 99%

“…The planned treatment was completed in 75.4% of patients in the XP arm and 81.7% in the XP-RT arm [11]. Other details of the ARTIST trial, including chemotherapy and RT protocols, were described in previous reports [8][9][10]. From the 458 patients enrolled, 106 tissue samples of 359 patients except 99 patients with stage I were available for evaluation in the present study.…”

Section: Patients and Samplesmentioning

confidence: 99%

“…According to this study, the mesenchymal (microsatellite-stable with epithelial-to-mesenchymal transition phenotype, MSS/EMT) tumors showed the worst prognosis with younger age at diagnosis, and higher recurrence rate with first presentation of peritoneal seeding. In addition to these clinical features of the mesenchymal subtype, the association of hypoxia and the increase in poly [adenosine diphosphate-ribose] polymerase-1 (PARP-1), which repairs deoxyribonucleic acid (DNA) damage, has been reported [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

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Outcomes of Radiotherapy for Mesenchymal and Non-Mesenchymal Subtypes of Gastric Cancer

Park

Lee

et al. 2020

Cancers

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Background: The purpose of this study was to evaluate the clinical outcomes following postoperative chemotherapy (XP) versus chemoradiotherapy (XP-RT) according to mesenchymal subtype based on RNA sequencing in gastric cancer (GC) in a cohort of the Adjuvant chemoRadioTherapy In Stomach Tumor (ARTIST) trial. Methods: Of the 458 patients enrolled in the ARTIST trial, formalin-fixed, paraffin-embedded (FFPE) specimens were available from 106 (23.1%) patients for RNA analysis. The mesenchymal subtype was classified according to a previously reported 71-gene MSS/EMT signature using the NanoString assay. Results: Of the 106 patients analyzed (50 in XP arm, 56 in XP-RT arm), 36 (34.0%) patients were categorized as mesenchymal subtype by NanoString assay. Recurrence-free survival (RFS, p = 0.009, hazard ratio (HR) = 2.11, 95% confidence interval (CI): 1.21–3.70) and overall survival (OS, p = 0.003, HR = 2.28, 95% CI: 1.31–3.96) were significantly lower in the mesenchymal subtype than in the non-mesenchymal subtype. In terms of post-operative radiotherapy (RT), mesenchymal subtype was not an independent variable to predict RFS or OS regardless to the assigned arm (XP with or without RT) in this patient cohort. However, there was a trend in the adjuvant XP arm, which showed higher OS than the XP-RT arm for the mesenchymal subtype and lower OS than the XP-RT arm for the non-mesenchymal subtype. Conclusions: We could not determine any significant differences between the mesenchymal and non-mesenchymal subtypes with respect to the effects of adjuvant XP with or without RT in gastric cancer following curative surgery.

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“…Black men with PCa are also 27% more likely to stain positive for AR and have 81% greater nuclear expression of AR 14 , 47 . The “EMT signature” also appears to correlate with resistance to radiation therapy and anti-androgens in a subset of PCa patients 48 . With this increased androgen responsiveness, one could posit that the tumorigenic epithelial cells within Black men would more likely undergo EMT and, thereby distant disease spread as a direct result of increased concentrations of TILs in the tumor microenvironment.…”

Section: Introductionmentioning

confidence: 99%

Technical Feasibility of Tissue Microarray (TMA) Analysis of Tumor-Associated Immune Response in Prostate Cancer

et al. 2018

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Introduction: The androgen receptor (AR) regulates immune-related epithelial-to-mesenchymal transition (EMT), and prostate cancer (PCa) metastasis. Primary tumor-infiltrating lymphocytes (TILs) [CD3+, CD4+, and CD8+ TILs] are potential prognostic indicators in PCa, and variations may contribute to racial disparities in tumor biology and PCa outcomes.Aim: To assess the technical feasibility of tumor microarray (TMA)-based methods to perform multi-marker TIL profiling in primary resected PCa.Methods: Paraffin-embedded tissue cores of histopathologically-confirmed primary PCa (n = 40; 1 TMA tissue specimen loss) were arrayed in triplicate on TMAs. Expression profiles of AR, CD3+, CD4+, and CD8+ TILs in normal prostate, and the center and periphery of both the tumor-dominant nodule and highest Gleason grade were detected by IHC and associated with clinical and pathological data using standard statistical methodology. An independent pathologist, blinded to the clinical data, scored all samples (percent and intensity of positive cells).Results: TMAs were constructed from 21 (53.8%) Black and 18 (46.2%) White males with completely-resected, primarily pT2 stage PCa [pT2a (n = 3; 7.7%); pT2b (n = 2; 5.1%); pT2c (n = 27; 69.2%); pT3a (n = 5; 12.8%); mean pre-op PSA = 8.17 ng/ml]. The CD3, CD4, CD8, and CD8/CD3 cellular protein expression differed from normal in the periphery of the dominant nodule, the center of the highest Gleason grade, and the periphery of the highest Gleason grade (P < 0.05). Correlations between TIL expression in the center and periphery of the dominant nodule, with corresponding center and periphery of the highest Gleason grade, respectively, were robust, and the magnitude of these correlations differed markedly by race (P < 0.05).Conclusions: Multi-marker (AR, CD3, CD4, CD8) profiling with IHC analysis of TMAs consisting of primary, non-metastatic resected prostate cancer is technically feasible in this pilot study. Future studies will evaluate primary tumor immunoscore using semi-quantitative, IHC-based methodology to assess differences in the spectrum, quantity, and/or localization of TILs, and to gain insights into racial disparities in PCa tumor biology and clinical outcomes.

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Predictive value of epithelial‐mesenchymal‐transition (EMT) signature and PARP‐1 in prostate cancer radioresistance

Abstract: Our results suggest that EMT programming effectors, integrated with the actin cytoskeleton regulator cofilin and mesenchymal PARP-1 expression profile provide a signature of potential predictive significance of therapeutic response to radiotherapy in a subset of prostate cancer patients.

Cited by 34 publications

References 44 publications

Sulfiredoxin as a Potential Therapeutic Target for Advanced and Metastatic Prostate Cancer

Sulfiredoxin as a Potential Therapeutic Target for Advanced and Metastatic Prostate Cancer

Outcomes of Radiotherapy for Mesenchymal and Non-Mesenchymal Subtypes of Gastric Cancer

Technical Feasibility of Tissue Microarray (TMA) Analysis of Tumor-Associated Immune Response in Prostate Cancer

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