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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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PAC120 xenograft tumor response to androgen deprivation treatment regimens.A) Kaplan-Meier analysis of hormone escape-free survival after continuous (white square, full line), intermittent (white square, dotted line) degarelix, bicalutamide plus degarelix (black triangle, full line) or flutamide plus degarelix (black triangle, dotted line). B) Tumor growth curves as a function of time in control (white cercle, full line), bicalutamide (white triangle, full line), flutamide (white triangle, dotted line),degarelix (white square, full line), bicalutamide plus degarelix (black triangle, full line) and flutamide plus degarelix (black triangle, dotted line); C i) PAC120 xenograft [x200], residual PAC120 tumor (300 days) ii)[x100], iii) [x400], AI variants with adenoid features (iv) [x100], amphicrine features (v) [x200], and mucosecretant features (vi) [x200].
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pone-0042252-g001: PAC120 xenograft tumor response to androgen deprivation treatment regimens.A) Kaplan-Meier analysis of hormone escape-free survival after continuous (white square, full line), intermittent (white square, dotted line) degarelix, bicalutamide plus degarelix (black triangle, full line) or flutamide plus degarelix (black triangle, dotted line). B) Tumor growth curves as a function of time in control (white cercle, full line), bicalutamide (white triangle, full line), flutamide (white triangle, dotted line),degarelix (white square, full line), bicalutamide plus degarelix (black triangle, full line) and flutamide plus degarelix (black triangle, dotted line); C i) PAC120 xenograft [x200], residual PAC120 tumor (300 days) ii)[x100], iii) [x400], AI variants with adenoid features (iv) [x100], amphicrine features (v) [x200], and mucosecretant features (vi) [x200].

Mentions: Continuous castration by degarelix arrested the growth of all PAC120 tumors. Recurrences were observed in 8/20 mice, in a median delay of 274 days [range 211–323] (Figure 1A). Intermittent castration was tested according to the following protocol: The first administration of degarelix reduced tumor volume in all animals (14/14, 100%). The second administration was given once tumor regrew of two-fold in volume, in a median delay of 119 days. Six tumors such treated did not respond (6/14, 43%) and 8 showed low response or stabilization. Kaplan Meier analysis showed an increased relative risk of recurrence of 14.5 (95% CI: 2.98–70.9, p<0.001, log-rank test) (Figure 1A and Table S2). Therefore, intermittent androgen deprivation increased the risk of recurrence and reduced time to progression as compared with continuous castration.


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)

PAC120 xenograft tumor response to androgen deprivation treatment regimens.A) Kaplan-Meier analysis of hormone escape-free survival after continuous (white square, full line), intermittent (white square, dotted line) degarelix, bicalutamide plus degarelix (black triangle, full line) or flutamide plus degarelix (black triangle, dotted line). B) Tumor growth curves as a function of time in control (white cercle, full line), bicalutamide (white triangle, full line), flutamide (white triangle, dotted line),degarelix (white square, full line), bicalutamide plus degarelix (black triangle, full line) and flutamide plus degarelix (black triangle, dotted line); C i) PAC120 xenograft [x200], residual PAC120 tumor (300 days) ii)[x100], iii) [x400], AI variants with adenoid features (iv) [x100], amphicrine features (v) [x200], and mucosecretant features (vi) [x200].
© Copyright Policy
Related In: Results  -  Collection

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

pone-0042252-g001: PAC120 xenograft tumor response to androgen deprivation treatment regimens.A) Kaplan-Meier analysis of hormone escape-free survival after continuous (white square, full line), intermittent (white square, dotted line) degarelix, bicalutamide plus degarelix (black triangle, full line) or flutamide plus degarelix (black triangle, dotted line). B) Tumor growth curves as a function of time in control (white cercle, full line), bicalutamide (white triangle, full line), flutamide (white triangle, dotted line),degarelix (white square, full line), bicalutamide plus degarelix (black triangle, full line) and flutamide plus degarelix (black triangle, dotted line); C i) PAC120 xenograft [x200], residual PAC120 tumor (300 days) ii)[x100], iii) [x400], AI variants with adenoid features (iv) [x100], amphicrine features (v) [x200], and mucosecretant features (vi) [x200].
Mentions: Continuous castration by degarelix arrested the growth of all PAC120 tumors. Recurrences were observed in 8/20 mice, in a median delay of 274 days [range 211–323] (Figure 1A). Intermittent castration was tested according to the following protocol: The first administration of degarelix reduced tumor volume in all animals (14/14, 100%). The second administration was given once tumor regrew of two-fold in volume, in a median delay of 119 days. Six tumors such treated did not respond (6/14, 43%) and 8 showed low response or stabilization. Kaplan Meier analysis showed an increased relative risk of recurrence of 14.5 (95% CI: 2.98–70.9, p<0.001, log-rank test) (Figure 1A and Table S2). Therefore, intermittent androgen deprivation increased the risk of recurrence and reduced time to progression as compared with continuous castration.

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