Identifying and treating ROBO1-ve /DOCK1+ve prostate cancer : An aggressive cancer subtype prevalent in African American patients
© 2020 Wiley Periodicals LLC..
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 AND RESULTS: 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/β-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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:80 |
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| Enthalten in: |
The Prostate - 80(2020), 13 vom: 30. Sept., Seite 1045-1057 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ferrari, Marina G [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 07.10.2020 Date Revised 13.12.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/pros.24018 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Ferrari, Marina G |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Identifying and treating ROBO1-ve /DOCK1+ve prostate cancer |b An aggressive cancer subtype prevalent in African American patients |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 07.10.2020 | ||
| 500 | |a Date Revised 13.12.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2020 Wiley Periodicals LLC. | ||
| 520 | |a 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 | ||
| 520 | |a METHODS AND RESULTS: 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/β-catenin activity, (b) transmigration of ROBO1deficient cells across endothelial lining, and (c) metastatic spread of ROBO1deficient cells through the vasculature of transgenicfl Zebrafish model | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a African American | |
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| 650 | 7 | |a Nerve Tissue Proteins |2 NLM | |
| 650 | 7 | |a RAC1 protein, human |2 NLM | |
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| 650 | 7 | |a rac GTP-Binding Proteins |2 NLM | |
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| 650 | 7 | |a EC 3.6.5.2 |2 NLM | |
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| 700 | 1 | |a Shabenah, Ashraf |e verfasserin |4 aut | |
| 700 | 1 | |a Mansini, Adrian P |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Li |e verfasserin |4 aut | |
| 700 | 1 | |a Murugan, Paari |e verfasserin |4 aut | |
| 700 | 1 | |a Davicioni, Elai |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jinhua |e verfasserin |4 aut | |
| 700 | 1 | |a Deng, Yibin |e verfasserin |4 aut | |
| 700 | 1 | |a Hoeppner, Luke H |e verfasserin |4 aut | |
| 700 | 1 | |a Warlick, Christopher A |e verfasserin |4 aut | |
| 700 | 1 | |a Konety, Badrinath R |e verfasserin |4 aut | |
| 700 | 1 | |a Saleem, Mohammad |e verfasserin |4 aut | |
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