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Risk of hormone escape in a human prostate cancer model depends on therapy modalities and can be reduced by tyrosine kinase inhibitors.

Guyader C, Céraline J, Gravier E, Morin A, Michel S, Erdmann E, de Pinieux G, Cabon F, Bergerat JP, Poupon MF, Oudard S - PLoS ONE (2012)

Bottom Line: AR amplification was found after complete blockade.Combination of castration with a Her-2/neu inhibitor decreased recurrence risk (0.17) and combination with an mTOR inhibitor prevented it.We postulated that Her-2/AKT pathways allowed salvage of tumor cells under castration and we demonstrated that their inhibition prevented tumor recurrence in our model.

View Article: PubMed Central - PubMed

Affiliation: Translational Research Department, Institut Curie, Paris, France.

ABSTRACT
Almost all prostate cancers respond to androgen deprivation treatment but many recur. We postulated that risk of hormone escape--frequency and delay--are influenced by hormone therapy modalities. More, hormone therapies induce crucial biological changes involving androgen receptors; some might be targets for escape prevention. We investigated the relationship between the androgen deprivation treatment and the risk of recurrence using nude mice bearing the high grade, hormone-dependent human prostate cancer xenograft PAC120. Tumor-bearing mice were treated by Luteinizing-Hormone Releasing Hormone (LHRH) antagonist alone, continuous or intermittent regimen, or combined with androgen receptor (AR) antagonists (bicalutamide or flutamide). Tumor growth was monitored. Biological changes were studied as for genomic alterations, AR mutations and protein expression in a large series of recurrent tumors according to hormone therapy modalities. Therapies targeting Her-2 or AKT were tested in combination with castration. All statistical tests were two-sided. Tumor growth was inhibited by continuous administration of the LH-RH antagonist degarelix (castration), but 40% of tumors recurred. Intermittent castration or complete blockade induced by degarelix and antiandrogens combination, inhibited tumor growth but increased the risk of recurrence (RR) as compared to continuous castration (RR(intermittent): 14.5, RR(complete blockade): 6.5 and 1.35). All recurrent tumors displayed new quantitative genetic alterations and AR mutations, whatever the treatment modalities. AR amplification was found after complete blockade. Increased expression of Her-2/neu with frequent ERK/AKT activation was detected in all variants. Combination of castration with a Her-2/neu inhibitor decreased recurrence risk (0.17) and combination with an mTOR inhibitor prevented it. Anti-hormone treatments influence risk of recurrence although tumor growth inhibition was initially similar. Recurrent tumors displayed genetic instability, AR mutations, and alterations of phosphorylation pathways. We postulated that Her-2/AKT pathways allowed salvage of tumor cells under castration and we demonstrated that their inhibition prevented tumor recurrence in our model.

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Protein expression of the androgen receptor (AR), human epidermal growth factor receptor 2 (Her-2/neu) and ratios of pAKT/AKT and pERK/ERK detected using A) Western blotting analysis in androgen-independent (AI) variants.Actin was used as a control for loading protein. B) Histograms representing the quantification of AR, Her-2/neu and ratios of pAKT/AKT and pERK/ERK normalized to actin and mean of PAC120 coming from various passages (expressed arbitrary units). AR (black bars) was expressed in PAC120 and all AI variants and Her-2/neu (dotted grey bars) was overexpressed in all AI variants. Either p-AKT/AKT (grey bars with full line) or pERK/ERK (white bars) were activated in AI variants. Abbreviations used to identify variants are explained in the legend of Figure 2.
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pone-0042252-g004: Protein expression of the androgen receptor (AR), human epidermal growth factor receptor 2 (Her-2/neu) and ratios of pAKT/AKT and pERK/ERK detected using A) Western blotting analysis in androgen-independent (AI) variants.Actin was used as a control for loading protein. B) Histograms representing the quantification of AR, Her-2/neu and ratios of pAKT/AKT and pERK/ERK normalized to actin and mean of PAC120 coming from various passages (expressed arbitrary units). AR (black bars) was expressed in PAC120 and all AI variants and Her-2/neu (dotted grey bars) was overexpressed in all AI variants. Either p-AKT/AKT (grey bars with full line) or pERK/ERK (white bars) were activated in AI variants. Abbreviations used to identify variants are explained in the legend of Figure 2.

Mentions: The AR protein level (normalized by actin) was increased in all AI variants (Figure 4). These data suggest that AR alterations are key events in tumor recurrence after androgen deprivation, required for prostate cancer cell survival.


Risk of hormone escape in a human prostate cancer model depends on therapy modalities and can be reduced by tyrosine kinase inhibitors.

Guyader C, Céraline J, Gravier E, Morin A, Michel S, Erdmann E, de Pinieux G, Cabon F, Bergerat JP, Poupon MF, Oudard S - PLoS ONE (2012)

Protein expression of the androgen receptor (AR), human epidermal growth factor receptor 2 (Her-2/neu) and ratios of pAKT/AKT and pERK/ERK detected using A) Western blotting analysis in androgen-independent (AI) variants.Actin was used as a control for loading protein. B) Histograms representing the quantification of AR, Her-2/neu and ratios of pAKT/AKT and pERK/ERK normalized to actin and mean of PAC120 coming from various passages (expressed arbitrary units). AR (black bars) was expressed in PAC120 and all AI variants and Her-2/neu (dotted grey bars) was overexpressed in all AI variants. Either p-AKT/AKT (grey bars with full line) or pERK/ERK (white bars) were activated in AI variants. Abbreviations used to identify variants are explained in the legend of Figure 2.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3412862&req=5

pone-0042252-g004: Protein expression of the androgen receptor (AR), human epidermal growth factor receptor 2 (Her-2/neu) and ratios of pAKT/AKT and pERK/ERK detected using A) Western blotting analysis in androgen-independent (AI) variants.Actin was used as a control for loading protein. B) Histograms representing the quantification of AR, Her-2/neu and ratios of pAKT/AKT and pERK/ERK normalized to actin and mean of PAC120 coming from various passages (expressed arbitrary units). AR (black bars) was expressed in PAC120 and all AI variants and Her-2/neu (dotted grey bars) was overexpressed in all AI variants. Either p-AKT/AKT (grey bars with full line) or pERK/ERK (white bars) were activated in AI variants. Abbreviations used to identify variants are explained in the legend of Figure 2.
Mentions: The AR protein level (normalized by actin) was increased in all AI variants (Figure 4). These data suggest that AR alterations are key events in tumor recurrence after androgen deprivation, required for prostate cancer cell survival.

Bottom Line: AR amplification was found after complete blockade.Combination of castration with a Her-2/neu inhibitor decreased recurrence risk (0.17) and combination with an mTOR inhibitor prevented it.We postulated that Her-2/AKT pathways allowed salvage of tumor cells under castration and we demonstrated that their inhibition prevented tumor recurrence in our model.

View Article: PubMed Central - PubMed

Affiliation: Translational Research Department, Institut Curie, Paris, France.

ABSTRACT
Almost all prostate cancers respond to androgen deprivation treatment but many recur. We postulated that risk of hormone escape--frequency and delay--are influenced by hormone therapy modalities. More, hormone therapies induce crucial biological changes involving androgen receptors; some might be targets for escape prevention. We investigated the relationship between the androgen deprivation treatment and the risk of recurrence using nude mice bearing the high grade, hormone-dependent human prostate cancer xenograft PAC120. Tumor-bearing mice were treated by Luteinizing-Hormone Releasing Hormone (LHRH) antagonist alone, continuous or intermittent regimen, or combined with androgen receptor (AR) antagonists (bicalutamide or flutamide). Tumor growth was monitored. Biological changes were studied as for genomic alterations, AR mutations and protein expression in a large series of recurrent tumors according to hormone therapy modalities. Therapies targeting Her-2 or AKT were tested in combination with castration. All statistical tests were two-sided. Tumor growth was inhibited by continuous administration of the LH-RH antagonist degarelix (castration), but 40% of tumors recurred. Intermittent castration or complete blockade induced by degarelix and antiandrogens combination, inhibited tumor growth but increased the risk of recurrence (RR) as compared to continuous castration (RR(intermittent): 14.5, RR(complete blockade): 6.5 and 1.35). All recurrent tumors displayed new quantitative genetic alterations and AR mutations, whatever the treatment modalities. AR amplification was found after complete blockade. Increased expression of Her-2/neu with frequent ERK/AKT activation was detected in all variants. Combination of castration with a Her-2/neu inhibitor decreased recurrence risk (0.17) and combination with an mTOR inhibitor prevented it. Anti-hormone treatments influence risk of recurrence although tumor growth inhibition was initially similar. Recurrent tumors displayed genetic instability, AR mutations, and alterations of phosphorylation pathways. We postulated that Her-2/AKT pathways allowed salvage of tumor cells under castration and we demonstrated that their inhibition prevented tumor recurrence in our model.

Show MeSH
Related in: MedlinePlus