MDV3100 effects on androgen receptor (AR) signaling and bone marrow testosterone concentration modulation: Apreliminary report.

Efstathiou, E.; Titus, Mark A.; Tsavachidou, Dimitra; Hoang, Anh; Κάρλου, Μαρία; Wen, Simeng; Troncoso, P.; Ashe, Robynne; Berman, Craig; Mohler, James L.; Logothetis, C.

doi:10.1200/jco.2011.29.15_suppl.4501

Cited by 21 publications

(15 citation statements)

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“…Higher baseline bone marrow and plasma testosterone level were also associated with PSA response (p<0.05) [15]. Studies noted above indicate that AR expression and function can change through tumor progression and may be affected by specific treatment agents with different mechanisms of action, such as the novel anti-androgens.…”

Section: Potential Biomarkers Of Response To Hormonal Therapy (Tabmentioning

confidence: 99%

Predicting response to hormonal therapy and survival in men with hormone sensitive metastatic prostate cancer

Grivas

Robins

Hussain

2013

Critical Reviews in Oncology/Hematology

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Androgen deprivation is the cornerstone of the management of metastatic prostate cancer. Despite several decades of clinical experience with this therapy there are no standard predictive biomarkers for response. Although several candidate genetic, hormonal, inflammatory, biochemical, metabolic biomarkers have been suggested as potential predictors of response and outcome, none has been prospectively validated nor has proven clinical utility to date. There is significant heterogeneity in the depth and duration of hormonal response and in the natural history of advanced disease; therefore to better optimize/individualize therapy and for future development, identification of biomarkers is critical. This review summarizes the current data on the role of several candidate biomarkers that have been evaluated in the advanced/metastatic disease setting.

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Section: Potential Biomarkers Of Response To Hormonal Therapy (Tabmentioning

confidence: 99%

Predicting response to hormonal therapy and survival in men with hormone sensitive metastatic prostate cancer

Grivas

Robins

Hussain

2013

Critical Reviews in Oncology/Hematology

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“…Clinical reports have shown that patients treated with enzalutamide have elevated testosterone levels in the bone marrow (13, 14). A cascade of enzymes is involved in the biosynthesis of intratumoral androgens, including CYP17A1, HSD3B and AKR1C3.…”

Section: Introductionmentioning

confidence: 99%

Intracrine Androgens and AKR1C3 Activation Confer Resistance to Enzalutamide in Prostate Cancer

et al. 2015

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The introduction of enzalutamide and abiraterone has led to improvement in the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, acquired resistance to enzalutamide and abiraterone therapies frequently develops within a short period in many patients. In the present study, we developed enzalutamide resistant prostate cancer cells in an effort to understand the mechanisms of resistance. Global gene expression analysis showed that steroid biosynthesis pathway is activated in enzalutamide resistant prostate cancer cells. One of the crucial steroidogenic enzymes, AKR1C3, was significantly elevated in enzalutamide resistant cells. In addition, AKR1C3 is highly expressed in metastatic and recurrent prostate cancer and in enzalutamide resistant prostate xenograft tumors. Liquid Chromatography-Mass Spectrometry (LC-MS) analysis of the steroid metabolites revealed that androgen precursors such as cholesterol, DHEA and progesterone, as well as androgens are highly up regulated in enzalutamide resistant prostate cancer cells compared to the parental cells. Knock down of AKR1C3 expression by shRNA or inhibition of AKR1C3 enzymatic activity by indomethacin resensitized enzalutamide resistant prostate cancer cells to enzalutamide treatment both in vitro and in vivo. In contrast, overexpression of AKR1C3 confers resistance to enzalutamide. Furthermore, the combination of indomethacin and enzalutamide resulted in significant inhibition of enzalutamide-resistant tumor growth. These results suggest that AKR1C3 activation is a critical resistance mechanism associated with enzalutamide resistance, targeting intracrine androgens and AKR1C3 will overcome enzalutamide resistance and improve survival of advanced prostate cancer patients.

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“…The ongoing phase II study of the combination of enzalutamide and abiraterone acetate in patients with CRPC with bone disease is supported by data that showed increased bone marrow testosterone in enzalutamidetreated patients and increased nuclear AR expression in abiraterone-treated patients, suggesting that these agents will work synergistically (NCT01650194; ref. 16). Finally, a phase Ib study of enzalutamide in combination with docetaxel has completed enrollment, with final reporting of data pending (NCT01565928).…”

Section: Future Developmentmentioning

confidence: 99%

Enzalutamide: A Novel Antiandrogen for Patients with Castrate-Resistant Prostate Cancer

Hoffman-Censits

Kelly

2013

Clinical Cancer Research

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Enzalutamide (MDV3100, Xtandi, Medivation\Astellas) is an oral inhibitor of androgen receptor signaling that blocks androgen receptor interaction, inhibits translocation of the androgen receptor to the nucleus, impairs androgen receptor binding to DNA, and inhibits coactivator recruitment and receptormediated DNA transcription. In a phase III randomized study comparing enzalutamide with placebo in men with progressive castration-resistant prostate cancer (CRPC) who were previously treated with docetaxel, enzalutamide showed an improvement in overall survival (18.4 vs. 13.6 months, HR, 0.63; P < 0.001). In addition, all secondary endpoints including proportion of patients with prostate-specific antigen (PSA) decline, soft-tissue response, quality-of-life response, time to PSA progression, radiographic progressionfree survival, and the time to the first radiographic skeletal event all significantly favored patients treated with enzalutamide. Fatigue, diarrhea, and hot flashes were common in patients treated with enzalutamide, with seizures reported in 5 (0.6%) of the patients. Enzalutamide is a novel therapy that very potently blocks the androgen signaling pathway, which is unregulated during the development of CRPC. The preclinical studies along with the pivotal trials that led to its approval by the U.S. Food and Drug Administration (FDA) in September 2012 will be reviewed.

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MDV3100 effects on androgen receptor (AR) signaling and bone marrow testosterone concentration modulation: Apreliminary report.

Cited by 21 publications

References 0 publications

Predicting response to hormonal therapy and survival in men with hormone sensitive metastatic prostate cancer

Predicting response to hormonal therapy and survival in men with hormone sensitive metastatic prostate cancer

Intracrine Androgens and AKR1C3 Activation Confer Resistance to Enzalutamide in Prostate Cancer

Enzalutamide: A Novel Antiandrogen for Patients with Castrate-Resistant Prostate Cancer

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