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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 combination treatment of castration plus tyrosine kinase inhibitors shown as A) escape-free survival (Kaplan-Meier analysis) where the median time to hormone escape after continuous treatment with degarelix (black square, full line) was 274 days and after combination of trastuzumab plus FE 200846 (cross, full line) was 351 days.B) tumor growth curves as a function of time in the control group (white cercle, full line) and in groups receiving everolimus 2 mg/kg three times a week (white diamond shape, dotted line), degarelix 10 mg/kg monthly (white square, full line), trastuzumab plus degarelix (cross, full line) or everolimus plus degarelix (black diamond-shaped, full line).
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pone-0042252-g005: PAC120 xenograft tumor response to combination treatment of castration plus tyrosine kinase inhibitors shown as A) escape-free survival (Kaplan-Meier analysis) where the median time to hormone escape after continuous treatment with degarelix (black square, full line) was 274 days and after combination of trastuzumab plus FE 200846 (cross, full line) was 351 days.B) tumor growth curves as a function of time in the control group (white cercle, full line) and in groups receiving everolimus 2 mg/kg three times a week (white diamond shape, dotted line), degarelix 10 mg/kg monthly (white square, full line), trastuzumab plus degarelix (cross, full line) or everolimus plus degarelix (black diamond-shaped, full line).

Mentions: Degarelix combined with trastuzumab significantly and drastically reduced the relative risk of recurrence to 0.17 (95% CI: 0.04–0.67, p = 0.005, log-rank test) (Figure 5A), and prolonged the median time to hormone escape from 274 to 351 days (Table S2) versus castration with degarelix alone. Tumor recurrence was observed in only 17% (4/24) of animals receiving the combination treatment. Trastuzumab as a single agent had no effect on the tumor growth.


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 combination treatment of castration plus tyrosine kinase inhibitors shown as A) escape-free survival (Kaplan-Meier analysis) where the median time to hormone escape after continuous treatment with degarelix (black square, full line) was 274 days and after combination of trastuzumab plus FE 200846 (cross, full line) was 351 days.B) tumor growth curves as a function of time in the control group (white cercle, full line) and in groups receiving everolimus 2 mg/kg three times a week (white diamond shape, dotted line), degarelix 10 mg/kg monthly (white square, full line), trastuzumab plus degarelix (cross, full line) or everolimus plus degarelix (black diamond-shaped, full line).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0042252-g005: PAC120 xenograft tumor response to combination treatment of castration plus tyrosine kinase inhibitors shown as A) escape-free survival (Kaplan-Meier analysis) where the median time to hormone escape after continuous treatment with degarelix (black square, full line) was 274 days and after combination of trastuzumab plus FE 200846 (cross, full line) was 351 days.B) tumor growth curves as a function of time in the control group (white cercle, full line) and in groups receiving everolimus 2 mg/kg three times a week (white diamond shape, dotted line), degarelix 10 mg/kg monthly (white square, full line), trastuzumab plus degarelix (cross, full line) or everolimus plus degarelix (black diamond-shaped, full line).
Mentions: Degarelix combined with trastuzumab significantly and drastically reduced the relative risk of recurrence to 0.17 (95% CI: 0.04–0.67, p = 0.005, log-rank test) (Figure 5A), and prolonged the median time to hormone escape from 274 to 351 days (Table S2) versus castration with degarelix alone. Tumor recurrence was observed in only 17% (4/24) of animals receiving the combination treatment. Trastuzumab as a single agent had no effect on the tumor growth.

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