Identifying and treating ROBO1-ve /DOCK1+ve prostate cancer: An aggressive cancer subtype prevalent in African American patients.
Prostate
; 80(13): 1045-1057, 2020 09.
Article
em En
| MEDLINE
| ID: mdl-32687658
ABSTRACT
BACKGROUND:
There is a need to develop novel therapies which could be beneficial to patients with prostate cancer (CaP) including those who are predisposed to poor outcome, such as African-Americans. This study investigates the role of ROBO1-pathway in predicting outcome and race-based disparity in patients with CaP. METHODS ANDRESULTS:
Aided by RNA sequencing-based DECIPHER-testing and immunohistochemical (IHC) analysis of tumors we show that ROBO1 is lost during the progressive stages of CaP, a prevalent feature in African-Americans. We show that the loss of ROBO1 predicts high-risk of recurrence, metastasis and poor outcome of androgen-deprivation therapy in radical prostatectomy-treated patients. These data identified an aggressive ROBO1deficient /DOCK1+ve sub-class of CaP. Combined genetic and IHC data showed that ROBO1 loss is accompanied by DOCK1/Rac1 elevation in grade-III/IV primary-tumors and Mets. We observed that the hypermethylation of ROBO1-promoter contributes to loss of expression that is highly prevalent in African-Americans. Because of limitations in restoring ROBO1 function, we asked if targeting the DOCK1 could be an ideal strategy to inhibit progression or treat ROBO1deficient metastatic-CaP. We tested the pharmacological efficacy of CPYPP, a selective inhibitor of DOCK1 under in vitro and in vivo conditions. Using ROBO1-ve and ROBO1+ve CaP models, we determined the median effective concentration of CPYPP for growth. DOCK1-inhibitor treatment significantly decreased the (a) Rac1-GTP/ß-catenin activity, (b) transmigration of ROBO1deficient cells across endothelial lining, and (c) metastatic spread of ROBO1deficient cells through the vasculature of transgenicfl Zebrafish model.CONCLUSION:
We suggest that ROBO1 status forms as predictive biomarker of outcome in high-risk populations such as African-Americans and DOCK1-targeting therapy has a clinical potential for treating metastatic-CaP.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Próstata
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Negro ou Afro-Americano
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Receptores Imunológicos
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Proteínas rac de Ligação ao GTP
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Proteínas do Tecido Nervoso
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article