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A novel HSP90 inhibitor delays castrate-resistant prostate cancer without altering serum PSA levels and inhibits osteoclastogenesis.

ABSTRACT: Prostate cancer responds initially to antiandrogen therapies; however, progression to castration-resistant disease frequently occurs. Therefore, there is an urgent need for novel therapeutic agents that can prevent the emergence of castrate-resistant prostate cancer (CRPC). HSP90 is a molecular chaperone involved in the stability of many client proteins including Akt and androgen receptor (AR). 17-Allylamino-17-demethoxy-geldanamycin (17-AAG) has been reported to inhibit tumor growth in various cancers; however, it induces tumor progression in the bone microenvironment.Cell growth, apoptosis, and AR transactivation were examined by crystal violet assay, flow cytometric, and luciferase assays, respectively. The consequence of HSP90 therapy in vivo was evaluated in LNCaP xenograft model. The consequence of PF-04928473 therapy on bone metastasis was studied using an osteoclastogenesis in vitro assay.PF-04928473 inhibits cell growth in a panel of prostate cancer cells, induces cell-cycle arrest at sub-G(1), and leads to apoptosis and increased caspase-3 activity. These biological events were accompanied by decreased activation of Akt and Erk as well as decreased expression of Her2, and decreased AR expression and activation in vitro. In contrast to 17-AAG, PF-04928473 abrogates RANKL-induced osteoclast differentiation by affecting NF-?B activation and Src phosphorylation. Finally, PF-04929113 inhibited tumor growth and prolonged survival compared with controls. Surprisingly, PF-04929113 did not reduce serum prostate-specific antigen (PSA) levels in vivo; in parallel, these decrease in tumor volume.These data identify significant anticancer activity of PF-04929113 in CRPC but suggest that serum PSA may not prove useful as pharmacodynamic tool for this drug.

SUBMITTER: Lamoureux F

PROVIDER: S-EPMC4437585 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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A novel HSP90 inhibitor delays castrate-resistant prostate cancer without altering serum PSA levels and inhibits osteoclastogenesis.

Lamoureux Francois F Thomas Christian C Yin Min-Jean MJ Kuruma Hidetoshi H Fazli Ladan L Gleave Martin E ME Zoubeidi Amina A

Clinical cancer research : an official journal of the American Association for Cancer Research 20110224 8

<h4>Purpose</h4>Prostate cancer responds initially to antiandrogen therapies; however, progression to castration-resistant disease frequently occurs. Therefore, there is an urgent need for novel therapeutic agents that can prevent the emergence of castrate-resistant prostate cancer (CRPC). HSP90 is a molecular chaperone involved in the stability of many client proteins including Akt and androgen receptor (AR). 17-Allylamino-17-demethoxy-geldanamycin (17-AAG) has been reported to inhibit tumor gr ...[more]

PMID: 21349995

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Project description:BackgroundPrognostic models in metastatic castrate resistant prostate cancer (mCRPC) may have clinical utility. Using data from PDS, we aimed to 1) validate a contemporary prognostic model (Templeton et al., 2014) 2) evaluate prognostic impact of concomitant medications and PSA decrease 3) evaluate factors associated with docetaxel toxicity.MethodsWe accessed data on 2,449 mCRPC patients in PDS. The existing model was validated with a continuous risk score, time-dependent receiver operating characteristic (ROC) curves, and corresponding time-dependent Area under the Curve (tAUC). The prognostic effects of concomitant medications and PSA response were assessed by Cox proportional hazards models. One year tAUC was calculated for multivariable prognostic model optimized to our data. Conditional logistic regression models were used to assess associations with grade 3/4 adverse events (G3/4 AE) at baseline and after cycle 1 of treatment.ResultsDespite limitations of the PDS data set, the existing model was validated; one year AUC, was 0.68 (95% CI 95% CI, .66 to .71) to 0.78 (95%CI, .74 to .81) depending on the subset of datasets used. A new model was constructed with an AUC of .74 (.72 to .77). Concomitant medications low molecular weight heparin and warfarin were associated with poorer survival, Metformin and Cox2 inhibitors were associated with better outcome. PSA response was associated with survival, the effect of which was greatest early in follow-up. Age was associated with baseline risk of G3/4 AE. The odds of experiencing G3/4 AE later on in treatment were significantly greater for subjects who experienced a G3/4 AE in their first cycle (OR 3.53, 95% CI 2.53-4.91, p < .0001).ConclusionDespite heterogeneous data collection protocols, PDS provides access to large datasets for novel outcomes analysis. In this paper, we demonstrate its utility for validating existing models and novel model generation including the utility of concomitant medications in outcome analyses, as well as the effect of PSA response on survival and toxicity prediction.

Dataset Information

A novel HSP90 inhibitor delays castrate-resistant prostate cancer without altering serum PSA levels and inhibits osteoclastogenesis.

Publications

A novel HSP90 inhibitor delays castrate-resistant prostate cancer without altering serum PSA levels and inhibits osteoclastogenesis.

Similar Datasets

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