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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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Unsupervised hierarchical clustering analysis on gene copy number alterations.There was no relationship between gene copy number alterations and the type of hormone treatment. The left hand column indicates numbered AI variants by treatment where de denotes degarelix, de-a degarelix plus antiandrogen (bicalutamide or flutamide), de-t degarelix plus trastuzumab. Green and red colors correspond to losses and gains of gene copy number, respectively. Yellow corresponds absence of difference in terms of gene copy number between AI variants and parental PAC120 DNA.
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pone-0042252-g002: Unsupervised hierarchical clustering analysis on gene copy number alterations.There was no relationship between gene copy number alterations and the type of hormone treatment. The left hand column indicates numbered AI variants by treatment where de denotes degarelix, de-a degarelix plus antiandrogen (bicalutamide or flutamide), de-t degarelix plus trastuzumab. Green and red colors correspond to losses and gains of gene copy number, respectively. Yellow corresponds absence of difference in terms of gene copy number between AI variants and parental PAC120 DNA.

Mentions: The chromosomal stability of PAC120 tumors through time and passages has been previously demonstrated [24]. We co-hybridized AI DNA with the parental PAC120 DNA to reveal the new alterations. Thirty-five minimal regions were altered in at least 5 (20%) of the 26 AI variants studied. Surprisingly, none of the alterations were common to all AI variants. Gene copy gains and losses are detailed in Table S3. The 26 AI variants were grouped by altered regions into five distinct groups using a hierarchical cluster analysis (Figure 2). However, we did not find any treatment-specific pattern of alterations associated with recurrences (Fisher exact test and Benjamini and Hochberg correction to adjust for multiple testing). These results show that androgen deprivation generated a random diversity of new genetic alterations but no specific pattern could be attributed to the type of treatment regimen. These alterations were stably acquired (data not shown).


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)

Unsupervised hierarchical clustering analysis on gene copy number alterations.There was no relationship between gene copy number alterations and the type of hormone treatment. The left hand column indicates numbered AI variants by treatment where de denotes degarelix, de-a degarelix plus antiandrogen (bicalutamide or flutamide), de-t degarelix plus trastuzumab. Green and red colors correspond to losses and gains of gene copy number, respectively. Yellow corresponds absence of difference in terms of gene copy number between AI variants and parental PAC120 DNA.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0042252-g002: Unsupervised hierarchical clustering analysis on gene copy number alterations.There was no relationship between gene copy number alterations and the type of hormone treatment. The left hand column indicates numbered AI variants by treatment where de denotes degarelix, de-a degarelix plus antiandrogen (bicalutamide or flutamide), de-t degarelix plus trastuzumab. Green and red colors correspond to losses and gains of gene copy number, respectively. Yellow corresponds absence of difference in terms of gene copy number between AI variants and parental PAC120 DNA.
Mentions: The chromosomal stability of PAC120 tumors through time and passages has been previously demonstrated [24]. We co-hybridized AI DNA with the parental PAC120 DNA to reveal the new alterations. Thirty-five minimal regions were altered in at least 5 (20%) of the 26 AI variants studied. Surprisingly, none of the alterations were common to all AI variants. Gene copy gains and losses are detailed in Table S3. The 26 AI variants were grouped by altered regions into five distinct groups using a hierarchical cluster analysis (Figure 2). However, we did not find any treatment-specific pattern of alterations associated with recurrences (Fisher exact test and Benjamini and Hochberg correction to adjust for multiple testing). These results show that androgen deprivation generated a random diversity of new genetic alterations but no specific pattern could be attributed to the type of treatment regimen. These alterations were stably acquired (data not shown).

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