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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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AR gene sequence showing mutations detected in AI variants A) after treatment with single-agent degarelix, B) after antiandrogens and C) after complete androgen blockade.Full underlines show mutations found in more than one tumor treated with the same agent. Mutations depicted with a blue, green or red background have previously been described in PAIS, CAIS and PCa, respectively.
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pone-0042252-g003: AR gene sequence showing mutations detected in AI variants A) after treatment with single-agent degarelix, B) after antiandrogens and C) after complete androgen blockade.Full underlines show mutations found in more than one tumor treated with the same agent. Mutations depicted with a blue, green or red background have previously been described in PAIS, CAIS and PCa, respectively.

Mentions: AR mutations were detected using a functional yeast-based assay as described previously [22]. No functional AR mutations were found in the PAC120 tumor but appeared in 28% (10/36) of AI variant tumors. An example of the profile that we obtained for AIde-a4 is shown in the Figure S3. Mutations occurred in 46%, 17%, and 25% after complete blockade, antiandrogens and degarelix, respectively (Table S4). AR cDNA sequencing revealed 30 different AR mutations (Figure 3, Table 1), of which 70% were located in the hinge region (HR) or in the ligand binding domain (LBD), 27% led to a truncated AR protein. Some AI variants displayed several mutations. Only Q693X was common to all of the different hormone treatments. The Q693X mutation, as well as the other premature stop codons in Table 1, leads to a truncated AR variant lacking the ligand-binding domain and AF-2. The Q693X AR variant has also been detected in human prostate cancer tumors (unpublished data). Truncated AR variants demonstrate constitutive transcriptional activities as previously reported [23]. They have been associated with castration-resistance as they can promote prostate cancer cell growth in vitro cell cultures and animal tumor models in the absence of androgens (Figure S4). Most mutations were novel.


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)

AR gene sequence showing mutations detected in AI variants A) after treatment with single-agent degarelix, B) after antiandrogens and C) after complete androgen blockade.Full underlines show mutations found in more than one tumor treated with the same agent. Mutations depicted with a blue, green or red background have previously been described in PAIS, CAIS and PCa, respectively.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0042252-g003: AR gene sequence showing mutations detected in AI variants A) after treatment with single-agent degarelix, B) after antiandrogens and C) after complete androgen blockade.Full underlines show mutations found in more than one tumor treated with the same agent. Mutations depicted with a blue, green or red background have previously been described in PAIS, CAIS and PCa, respectively.
Mentions: AR mutations were detected using a functional yeast-based assay as described previously [22]. No functional AR mutations were found in the PAC120 tumor but appeared in 28% (10/36) of AI variant tumors. An example of the profile that we obtained for AIde-a4 is shown in the Figure S3. Mutations occurred in 46%, 17%, and 25% after complete blockade, antiandrogens and degarelix, respectively (Table S4). AR cDNA sequencing revealed 30 different AR mutations (Figure 3, Table 1), of which 70% were located in the hinge region (HR) or in the ligand binding domain (LBD), 27% led to a truncated AR protein. Some AI variants displayed several mutations. Only Q693X was common to all of the different hormone treatments. The Q693X mutation, as well as the other premature stop codons in Table 1, leads to a truncated AR variant lacking the ligand-binding domain and AF-2. The Q693X AR variant has also been detected in human prostate cancer tumors (unpublished data). Truncated AR variants demonstrate constitutive transcriptional activities as previously reported [23]. They have been associated with castration-resistance as they can promote prostate cancer cell growth in vitro cell cultures and animal tumor models in the absence of androgens (Figure S4). Most mutations were novel.

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