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Prostate cancer androgen receptor activity dictates efficacy of bipolar androgen therapy through MYC [RNA-seq: patient biopsies]

ABSTRACT: Prostate cancer androgen receptor activity dictates efficacy of bipolar androgen therapy through MYC [RNA-seq: patient biopsies]

PROVIDER: PRJNA954869 | ENA |

REPOSITORIES: ENA

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Prostate cancer androgen receptor activity dictates efficacy of bipolar androgen therapy through MYC

Project description:Prostate cancer androgen receptor activity dictates efficacy of bipolar androgen therapy through MYC

| PRJNA880855 | ENA

Prostate cancer androgen receptor activity dictates efficacy of bipolar androgen therapy through MYC [RNA-seq]

Project description:Prostate cancer androgen receptor activity dictates efficacy of bipolar androgen therapy through MYC [RNA-seq]

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Prostate cancer androgen receptor activity dictates efficacy of bipolar androgen therapy through MYC [ATAC-seq]

Project description:Prostate cancer androgen receptor activity dictates efficacy of bipolar androgen therapy through MYC [ATAC-seq]

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Prostate cancer androgen receptor activity dictates efficacy of bipolar androgen therapy through MYC [RNA-seq: patient biopsies]

Project description:Testosterone is the canonical growth factor of prostate cancer but can paradoxically suppress its growth when present at supraphysiological levels. We have previously demonstrated that the cyclical administration of supraphysiological androgen (SPA), entitled Bipolar Androgen Therapy (BAT), can result in tumor regression and clinical benefit for patients with castration-resistant prostate cancer. However, predictors and mechanisms of response and resistance have been ill-defined. Here we show that growth inhibition of prostate cancer models by SPA requires high androgen receptor (AR) activity and is driven in part by downregulation of MYC. Using matched sequential patient biopsies, we show that high pre-treatment AR activity predicts downregulation of MYC, clinical response, and prolonged progression-free and overall survival for patients on BAT. BAT induced strong downregulation of AR in all patients, which is shown to be a primary mechanism of acquired resistance to SPA. Acquired resistance can be overcome by alternating SPA with the AR inhibitor enzalutamide, which induces adaptive upregulation of AR and re-sensitizes prostate cancer to SPA. This work identifies high AR activity score as a predictive biomarker of response to BAT and supports a new treatment paradigm for prostate cancer involving alternating between AR inhibition and activation

2023-04-12 | GSE229555 | GEO

Prostate cancer androgen receptor activity dictates efficacy of bipolar androgen therapy through MYC [RNA-seq]

2022-11-01 | GSE213443 | GEO

Prostate cancer androgen receptor activity dictates efficacy of bipolar androgen therapy through MYC [ATAC-seq]

2022-11-01 | GSE213437 | GEO

Androgen receptor activity in prostate cancer dictates efficacy of bipolar androgen therapy through MYC.

Project description:Testosterone is the canonical growth factor of prostate cancer but can paradoxically suppress its growth when present at supraphysiological levels. We have previously demonstrated that the cyclical administration of supraphysiological androgen (SPA), termed bipolar androgen therapy (BAT), can result in tumor regression and clinical benefit for patients with castration-resistant prostate cancer. However, predictors and mechanisms of response and resistance have been ill defined. Here, we show that growth inhibition of prostate cancer models by SPA required high androgen receptor (AR) activity and were driven in part by downregulation of MYC. Using matched sequential patient biopsies, we show that high pretreatment AR activity predicted downregulation of MYC, improved clinical response, and prolonged progression-free and overall survival for patients on BAT. BAT induced strong downregulation of AR in all patients, which is shown to be a primary mechanism of acquired resistance to SPA. Acquired resistance was overcome by alternating SPA with the AR inhibitor enzalutamide, which induced adaptive upregulation of AR and resensitized prostate cancer to SPA. This work identifies high AR activity as a predictive biomarker of response to BAT and supports a treatment paradigm for prostate cancer involving alternating between AR inhibition and activation.

| S-EPMC9711876 | biostudies-literature

Prostate cancer androgen receptor activity dictates efficacy of bipolar androgen therapy through MYC

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-11-01 | GSE213444 | GEO

Sexual dimorphism of gut microbiota dictates therapeutics efficacy of radiation injuries

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Dual targeting of the androgen receptor and PI3K/AKT/mTOR pathways in prostate cancer elicits improved anti-tumor efficacy and apoptosis

Project description:Both the PI3K/AKT/mTOR and androgen receptor (AR) signaling pathways play essential roles in prostate cancer. We compared the impact of PI3K/AKT/mTOR pathway inhibitors with different selectivity profiles on in vitro cell proliferation and apoptosis induction, and observed the strongest effects in androgen-sensitive prostate cancer models. Combination treatment with the AR inhibitor darolutamide led to enhanced apoptosis in these cell lines, with most pronounced effects of the pan-PI3K inhibitor copanlisib. Transcriptomic analysis performed in the androgen-sensitive VCaP cell line revealed that gene expression was more affected by the co-treatment with darolutamide and copanlisib, compared to single agents. A comprehensive reversal of the androgen response and the mTORC1 transcriptional programs was observed. The combination treatment also markedly induced DNA damage. An in vivo efficacy study performed using LuCaP 35, an androgen-sensitive patient-derived prostate cancer model, indicated superior efficacy after combined treatment with copanlisib and darolutamide. Immunohistochemistry analysis of treated tumors furthermore showed increased apoptosis. Altogether these data demonstrate that blocking the PI3K/AKT/mTOR and AR pathways with potent inhibitors has superior anti-tumor efficacy and induces apoptosis in androgen-sensitive prostate cancer models.

2024-01-22 | GSE245454 | GEO

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