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Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion.

ABSTRACT: Androgen deprivation therapy remains a critical component of treatment for men with advanced prostate cancer, and data support its use in metastatic disease and in conjunction with surgery or radiation in specific settings. Alternatives to standard androgen deprivation therapy, such as intermittent androgen suppression and estrogen therapy, hold the potential to improve toxicity profiles while maintaining clinical benefit. Current androgen deprivation strategies seem to incompletely suppress androgen levels and androgen-receptor-mediated effects at the tissue level. Advances in the understanding of mechanisms that contribute to castration-resistant prostate cancer are leading to rationally designed therapies targeting androgen metabolism and the androgen receptor. The results of large trials investigating the optimization of primary androgen deprivation therapy, including evaluation of intermittent androgen suppression and phase III studies of novel androgen synthesis inhibitors, such as abiraterone acetate, are eagerly awaited.

SUBMITTER: Harris WP

PROVIDER: S-EPMC2981403 | biostudies-other | 2009 Feb

REPOSITORIES: biostudies-other

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Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion.

Harris William P WP Mostaghel Elahe A EA Nelson Peter S PS Montgomery Bruce B

Nature clinical practice. Urology 20090201 2

Androgen deprivation therapy remains a critical component of treatment for men with advanced prostate cancer, and data support its use in metastatic disease and in conjunction with surgery or radiation in specific settings. Alternatives to standard androgen deprivation therapy, such as intermittent androgen suppression and estrogen therapy, hold the potential to improve toxicity profiles while maintaining clinical benefit. Current androgen deprivation strategies seem to incompletely suppress and ...[more]

PMID: 19198621

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Project description:Various molecular mechanisms play a role in the development of resistance to androgen deprivation therapy in castration-resistant prostate cancer (CRPC).To understand the mechanisms and biological pathways associated with the progression of prostate cancer (PCa) under systemic androgen depletion or administration of the novel antiandrogens abiraterone, enzalutamide, and ARN-509. This review also examines the introduction of novel combinational approaches for patients with CRPC.PubMed was the data source. Keywords for the search were castrate resistant prostate cancer, abiraterone, enzalutamide resistance mechanisms, resistance to androgen deprivation, AR mutations, amplifications, splice variants, and AR alterations. Papers published before 1990 were excluded from the review, and only English-language papers were included.This review summarizes the current literature regarding the mechanisms implicated in the development of CRPC and the acquisition of resistance to novel antiandrogen axis agents. The review focuses on androgen biosynthesis in the tumor microenvironment, androgen receptor (AR) alterations and post-transcriptional modifications, the role of glucocorticoid receptor, and alternative oncogenic signaling that is derepressed on maximum AR inhibition and thus promotes cancer survival and progression.The mechanisms implicated in the development of resistance to AR inhibition in PCa are multiple and complex, involving virtually all classes of genomic alteration and leading to a host of selective/adaptive responses. Combinational therapeutic approaches targeting both AR signaling and alternative oncogenic pathways may be reasonable for patients with CRPC.We looked for mechanisms related to the progression of PCa in patients undergoing hormonal therapy and treatment with novel drugs targeting the AR. Based on recent data, combining maximal AR inhibition with novel agents targeting other tumor-compensatory, non-AR-related pathways may improve the survival and quality of life of patients with castration-resistant PCa.

Project description:BACKGROUND:For specific clinical indications, androgen deprivation therapy (ADT) will induce disease prostate cancer (PC) regression, relieve symptoms and prolong survival; however, ADT has a well-described range of side effects, which may have a detrimental effect on the patient's quality of life, necessitating additional interventions or changes in PC treatment. The risk-benefit analysis for initiating ADT in PC patients throughout the PC disease continuum warrants review. METHODS:A 14-member panel comprised of urologic and medical oncologists were chosen for an expert review panel, to provide guidance on a more judicious use of ADT in advanced PC patients. Panel members were chosen based upon their academic and community experience and expertise in the management of PC patients. Four academic members of the panel served as group leaders; the remaining eight panel members were from Large Urology Group Practice Association practices with proven experience in leading their advanced PC clinics. The panel members were assigned to four separate working groups, and were tasked with addressing the role of ADT in specific PC settings. RESULTS:This article describes the practical recommendations of an expert panel for the use of ADT throughout the PC disease continuum, as well as an algorithm summarizing the key recommendations. The target for this publication is all providers (urologists, medical oncologists, radiation oncologists, or advanced practice providers) who evaluate and manage advanced PC patients, regardless of their practice setting. CONCLUSION:The panel has provided recommendations for monitoring PC patients while on ADT, recognizing that PC patients will progress despite testosterone suppression and, therefore, early identification of conversion from castrate-sensitive to castration resistance is critical. Also, the requirement to both identify and mitigate side effects of ADT as well as the importance of quality of life maintenance are essential to the optimization of patient care, especially as more combinatorial therapeutic strategies with ADT continue to emerge.

Project description:BACKGROUND:Prostate cancer (PCa), the second most common cancer affecting men worldwide, shows a broad spectrum of biological and clinical behaviour representing the epiphenomenon of an extreme heterogeneity. Androgen deprivation therapy is the mainstay of treatment for advanced forms but after few years the majority of patients progress to castration-resistant prostate cancer (CRPC), a lethal form that poses considerable therapeutic challenges. METHODS:Western blotting, immunocytochemistry, invasion and reporter assays, and in vivo studies were performed to characterize androgen resistant sublines phenotype in comparison to the parental cell line LNCaP. RNA microarray, mass spectrometry, integrative transcriptomic and proteomic differential analysis coupled with GeneOntology and multivariate analyses were applied to identify deregulated genes and proteins involved in CRPC evolution. RESULTS:Treating the androgen-responsive LNCaP cell line for over a year with 10 ?M bicalutamide both in the presence and absence of 0.1 nM 5-?-dihydrotestosterone (DHT) we obtained two cell sublines, designated PDB and MDB respectively, presenting several analogies with CRPC. Molecular and functional analyses of PDB and MDB, compared to the parental cell line, showed that both resistant cell lines were PSA low/negative with comparable levels of nuclear androgen receptor devoid of activity due to altered phosphorylation; cell growth and survival were dependent on AKT and p38MAPK activation and PARP-1 overexpression; their malignant phenotype increased both in vitro and in vivo. Performing bioinformatic analyses we highlighted biological processes related to environmental and stress adaptation supporting cell survival and growth. We identified 15 proteins that could direct androgen-resistance acquisition. Eleven out of these 15 proteins were closely related to biological processes involved in PCa progression. CONCLUSIONS:Our models suggest that environmental factors and epigenetic modulation can activate processes of phenotypic adaptation driving drug-resistance. The identified key proteins of these adaptive phenotypes could be eligible targets for innovative therapies as well as molecules of prognostic and predictive value.

Dataset Information

Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion.

Publications

Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion.

Similar Datasets

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