Validation of a Metastatic Assay using biopsies to improve risk stratification in patients with prostate cancer treated with radical radiation therapy

Jain, Suneil; Lyons, C.; Walker, Steven M.; McQuaid, Stephen; Hynes, Seán O.; Mitchell, D.; Pang, Brendan; Logan, Gemma E.; McCavigan, Andrena; O’Rourke, Declan; McArt, Darragh G.; McDade, Simon S.; Mills, Ian G.; Prise, Kevin M.; Knight, Laura; Steele, Christopher; Medlow, Paul; Berge, Viktor; Katz, Betina; Loblaw, D.A.; Harkin, D. Paul; James, Jacqueline; O’Sullivan, Joe M.; Kennedy, Richard D.; Waugh, David J.

doi:10.1093/annonc/mdx637

Cited by 82 publications

(166 citation statements)

References 20 publications

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“…Further analysis was performed on a second dataset to determine the direct relevance of this gene cluster with respect to radiotherapy response. Analysis was conducted on a transcriptomic profile derived from the FASTMAN retrospective radiotherapy patient sample cohort (Jain, Lyons et al, 2018). This cohort of 248 diagnostic biopsy samples has a median follow-up data of >100 months.…”

Section: Resultsmentioning

confidence: 99%

Targeting CXCR1 and CXCR2 to overcome radiotherapy resistance in PTEN-deficient prostate carcinoma

Ong

et al. 2020

Preprint

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Functional impairment of the tumour-suppressor PTEN is common in primaryprostate cancer and has been linked to relapse post-radiotherapy (RT). Pre-clinical modelling supports elevated CXC-chemokine signaling as a critical mediator of PTEN-depleted disease progression and therapeutic resistance. We assessed the correlation of PTEN-deficiency with CXC-chemokine signaling and its association with clinical outcomes. Gene expression analysis characterized a PTEN LOW /CXCR1 HIGH /CXCR2 HIGH cluster of tumors that associates with earlier timeto-biochemical recurrence (HR 5.87 and HR 2.65 respectively) and development of systemic metastasis (HR 3.51). In vitro, CXCL-signaling was further amplified following exposure of PTEN-deficient prostate cancer cell lines to ionizing radiation (IR). Inhibition of CXCR1/2-signaling in PTEN-depleted cell-based models increased IR-sensitivity. In vivo, administration of a CXCR1/2-targeted pepducin (x1/2pal-i3), orCXCR2-specific antagonist (AZD5069), in combination with IR to PTEN-deficient xenografts attenuated tumor growth and progression compared to control or IR alone. Post-mortem analysis confirmed that x1/2pal-i3 administration attenuated IRinduced CXCL-signaling and anti-apoptotic protein expression. Interventions targeting CXC-chemokine signaling may provide an effective strategy to combine with radiotherapy, in both locally-advanced and oligometastatic-prostate cancers, with known presence of PTEN-deficient foci.Thus, we adopted the hypothesis that exposure to ionizing radiation (IR) would similarly induce chemokine-signaling and that this would have a profound impact in modulating the sensitivity of PTEN-deficient tumors to radiation.The objective of this comprehensive study, employing clinical datasets and established in vitro and in vivo models, was to characterize whether stress-induced potentiation of CXCR1/2-signaling may underpin the adverse response of PTENdeficient prostate cancer to radiation and to potentially explain biological mechanisms related to increased clinical relapse reported in PTEN-deficient tumors. MATERIALS AND METHODS Cell cultureAuthenticated DU145, LNCaP, C42, C42B, PC3 and 22Rv1 CaP cells were obtained from ATCC. DU145 cells were manipulated as previously described to generate isogenic PTEN-expressing NT01 cells and PTEN-deficient sh11.02 cells (Maxwell et al., 2013). PC3 were manipulated as previously described so that PTEN-expression can be reconstituted following exposure to tetracycline (Maxwell et al., 2013). PTENdepleted 22RV1 cells were generated following lentiviral transfection of HuSh-29 pre-designed PTEN shRNA pGFP-V-RS constructs (Origene, Rockville, MD, USA), and selected under puromycin selection pressure at a final concentration of 0.5 μg/ml. Cell line authenticity was confirmed by STR genotyping (July 2019) and mycoplasma testing was performed every 4-6 weeks (MycoAlert, Lonza). ELISACells were plated into six-well plates at a density of 5 x 10 5 cells per well and allowed to adhere overnight. After 24H, cells were irradiated and med...

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Section: Resultsmentioning

confidence: 99%

Targeting CXCR1 and CXCR2 to overcome radiotherapy resistance in PTEN-deficient prostate carcinoma

Ong

et al. 2020

Preprint

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“…Nevertheless, this work adds to other studies that have reported on biopsy-based genomic signatures that predict for aggressive localized PCa, although most of these studies used mixed cohorts of intermediate-and high-risk PCa that were predominantly treated with ADT-RT. 15,23,24 Our study is therefore informative; beyond prognostication it provides potentially actionable information by focusing solely on IR-PCa, for which current guidelines reflect the clinical challenge of DE-RT alone versus systemic (ADT) and/or local (brachytherapy boost) intensification.…”

Section: Discussionmentioning

confidence: 99%

Genomic Classifier for Guiding Treatment of Intermediate-Risk Prostate Cancers to Dose-Escalated Image Guided Radiation Therapy Without Hormone Therapy

Berlin

Murgić

Hosni

et al. 2019

International Journal of Radiation Oncology*Biology*Physics

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“…Finally, the model was validated in another GEO dataset (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE116918) including 248 patients and The Cancer Genome Atlas (TCGA) dataset including 499 patients (https://portal.gdc.cancer.gov/). 25 And the prognostic value of the multigene model was also evaluated compared with T stage in http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE70769.…”

Section: Methodsmentioning

confidence: 99%

A four‐gene signature associated with clinical features can better predict prognosis in prostate cancer

et al. 2020

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Prostate cancer (PCa) is one of the most deadly urinary tumors in men globally, and the 5‐year over survival is poor due to metastasis of tumor. It is significant to explore potential biomarkers for early diagnosis and personalized therapy of PCa. In the present study, we performed an integrated analysis based on multiple microarrays in the Gene Expression Omnibus (GEO) dataset and obtained differentially expressed genes (DEGs) between 510 PCa and 259 benign issues. The weighted correlation network analysis indicated that prognostic profile was the most relevant to DEGs. Then, univariate and multivariate COX regression analyses were conducted and four prognostic genes were obtained to establish a four‐gene prognostic model. And the predictive effect and expression profiles of the four genes were well validated in another GEO dataset, The Cancer Genome Atlas and the Human Protein Atlas datasets. Furthermore, combination of four‐gene model and clinical features was analyzed systematically to guide the prognosis of patients with PCa to a largest extent. In summary, our findings indicate that four genes had important prognostic significance in PCa and combination of four‐gene model and clinical features could achieve a better prediction to guide the prognosis of patients with PCa.

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Validation of a Metastatic Assay using biopsies to improve risk stratification in patients with prostate cancer treated with radical radiation therapy

Cited by 82 publications

References 20 publications

Targeting CXCR1 and CXCR2 to overcome radiotherapy resistance in PTEN-deficient prostate carcinoma

Targeting CXCR1 and CXCR2 to overcome radiotherapy resistance in PTEN-deficient prostate carcinoma

Genomic Classifier for Guiding Treatment of Intermediate-Risk Prostate Cancers to Dose-Escalated Image Guided Radiation Therapy Without Hormone Therapy

A four‐gene signature associated with clinical features can better predict prognosis in prostate cancer

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