Cytochrome P17 Inhibition With Ketoconazole As Treatment for Advanced Granulosa Cell Ovarian Tumor

García-Donás, Jesús; Hurtado, Alicia; García-Casado, Zaida; Albareda, Judit; Löpez‐Guerrero, José Antonio; Alemany, Isabel; Grande, Enrique; Cámara, Juan Carlos; Hernando, Susana

doi:10.1200/jco.2012.45.0346

Cited by 18 publications

(15 citation statements)

References 10 publications

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“…65 In addition, the inhibition of CYP17 by ketoconazole also exhibited tumor-suppressive effects in ovarian cancer. 66 These results suggest that CYP17A1 inhibition is a potential target for the treatment of cancer patients. However, studies of tumor steroidogenesis have mainly focused on prostate cancer, and the effects of drugs targeting steroidogenic enzymes in other types of cancer have rarely been evaluated.…”

Section: Discussionmentioning

confidence: 91%

Upregulation of CYP17A1 by Sp1-mediated DNA demethylation confers temozolomide resistance through DHEA-mediated protection in glioma

et al. 2017

Oncogenesis

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Steroidogenesis-mediated production of neurosteroids is important for brain homeostasis. Cytochrome P450 17A1 (CYP17A1), which converts pregnenolone to dehydroepiandrosterone (DHEA) in endocrine organs and the brain, is required for prostate cancer progression and acquired chemotherapeutic resistance. However, whether CYP17A1-mediated DHEA synthesis is involved in brain tumor malignancy, especially in glioma, the most prevalent brain tumor, is unknown. To investigate the role of CYP17A1 in glioma, we determined that CYP17A1 expression is significantly increased in gliomas, which secrete more DHEA than normal astrocytes. We found that as gliomas became more malignant, both CYP17A1 and DHEA were significantly upregulated in temozolomide (TMZ)-resistant cells and highly invasive cells. In particular, the increase of CYP17A1 was caused by Sp1-mediated DNA demethylation, whereby Sp1 competed with DNMT3a for binding to the CYP17A1 promoter in TMZ-resistant glioma cells. CYP17A1 was required for the development of glioma cell invasiveness and resistance to TMZ-induced cytotoxicity. In addition, DHEA markedly attenuated TMZ-induced DNA damage and apoptosis. Together, our results suggest that components of the Sp1–CYP17A1–DHEA axis, which promotes the development of TMZ resistance, may serve as potential biomarkers and therapeutic targets in recurrent glioma.

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Section: Discussionmentioning

confidence: 91%

Upregulation of CYP17A1 by Sp1-mediated DNA demethylation confers temozolomide resistance through DHEA-mediated protection in glioma

et al. 2017

Oncogenesis

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“…Inhibition of this enzyme may thus reverse the effect of FOXL2 mutation. Additional inhibition of CYP17 may be achieved by novel agents such as abiraterone and ketoconazole [ 22 ], and therapies targeting this mechanism may prove to be more useful and less toxic than traditional chemotherapy [ 5 ]. Other novel potential targets (vascular endothelial growth factor (VEGF), HER2) are being investigated.…”

Section: Discussionmentioning

confidence: 99%

Is adjuvant chemotherapy beneficial for patients with FIGO stage IC adult granulosa cell tumor of the ovary?

Wang

Xiang

et al. 2018

J Ovarian Res

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BackgroundTo evaluate the association between adjuvant chemotherapy and clinical outcomes in patients with stage IC adult granulosa cell tumor (AGCT).MethodsWe performed a retrospective study of patients with stage IC AGCT diagnosed at our hospital from January 1985 to September 2015. We analyzed descriptive statistics, and performed univariate and multivariate and Kaplan–Meier survival analyses.ResultsSixty stage IC AGCT patients were identified, including 28 in the no adjuvant chemotherapy group (NACG) and 32 in the adjuvant chemotherapy group (ACG). The median follow-up time was 88 months (range: 9–334 months). Sixteen patients developed recurrences, including nine in the NACG and seven in the ACG groups. Univariate analysis identified incomplete surgical staging and initial treatment place as associated with disease-free survival (DFS) (P = 0.003 and 0.038, respectively). Incomplete surgical staging remained a risk factor for recurrence in multivariate analysis (hazard ratio (HR) = 3.883, 95% confidence interval (CI): 1.123–13.430, P = 0.032). The 5-year DFS rates in the NACG and ACG groups were 76.3% and 87.5% respectively (P = 0.197). Adjuvant chemotherapy was thus not associated with improved DFS. Furthermore, the number of chemotherapy cycles was not associated with recurrence rate (≤3 cycles vs. > 3 cycles, HR = 0.613, 95% CI: 0.112–3.351, P = 0.572).ConclusionAdministration of adjuvant chemotherapy does not improve DFS in patients with stage IC AGCT. Further studies with larger samples involving multi-institutional collaboration are needed to validate new treatment regimens for this disease.

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“…The potential serious toxicity of administered BEP chemotherapy such as myelosuppression and pulmonary disorders with a lack of obvious benefit suggests that new studies are needed to address the question of decision to administer chemotherapy in early-stage AGCT [ 39 ]. FOXL2 mutation was associated with increased CYP17 expression, and inhibition of this enzyme may be achieved by novel agents such as abiraterone and ketoconazole [ 40 ]. This new potential target for future therapeutics may prove to be more useful and less toxic and maybe could be considered in the adjuvant setting.…”

Section: Discussionmentioning

confidence: 99%

Adult Granulosa Cell Tumors of the Ovary: A Retrospective Study of 36 FIGO Stage I Cases with Emphasis on Prognostic Pathohistological Features

Babarović

Franin

Klarić

et al. 2018

Analytical Cellular Pathology

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Objective Adult granulosa cell tumors (AGCTs) represent 2%–5% of all ovarian malignancies. The aim of this study was to analyze clinical and pathohistological parameters and their impact on recurrence, overall, and disease-free survival in FIGO stage I AGCT patients. Methods The tumor specimens analyzed in this retrospective study were obtained from a total of 36 patients with diagnosis of ovarian AGCT surgically treated at the Department of Gynecology, Rijeka University Hospital Centre, between 1994 and 2012. Clinical, pathological, and follow-up data were collected. Results The mean age at diagnosis was 54.5 years with a range of 24–84. The majority of the patients, 30 (83%), were in FIGO stage IA, 3 (8%) in stage IC1, 1 (3%) in stage IC2, and 2 (6%) in stage IC3. During follow-up period (median 117.5 months, range 26–276), recurrence occurred in 4 patients (12%) with 2 deaths of the disease recorded. In univariate analysis, the 5-year survival rates were significantly shorter in patients with FIGO substage IC (p = 0.019), with positive LVSI (p = 0.022), with presence of necrosis (p = 0.040), and with hemorrhage (p = 0.017). In univariate analysis, the 5-year disease-free survival rates were significantly shorter in patients treated with fertility surgery (p = 0.004), with diffuse growth pattern (p = 0.012), with moderate and severe nuclear atypia (p = 0.032), and with presence of hemorrhage (p = 0.022). FIGO substage IC proved to be independent predictor for recurrence (OR = 16.87, p = 0.015, and OR = 23.49, p = 0.023, resp.) and disease-free survival (p = 0.0002; HR 20.84, p = 0.02) at the uni- and multivariate analyses. Conclusions FIGO substage IC is predictive of recurrence and disease-free survival in patients with early-stage AGCTs. LVSI, presence of necrosis and hemorrhage, diffuse growth pattern, and nuclear atypia in AGCTs seem to be associated with overall and disease-free survival, so these pathological features should be taken into consideration when managing patients with AGCT.

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Cytochrome P17 Inhibition With Ketoconazole As Treatment for Advanced Granulosa Cell Ovarian Tumor

Cited by 18 publications

References 10 publications

Upregulation of CYP17A1 by Sp1-mediated DNA demethylation confers temozolomide resistance through DHEA-mediated protection in glioma

Upregulation of CYP17A1 by Sp1-mediated DNA demethylation confers temozolomide resistance through DHEA-mediated protection in glioma

Is adjuvant chemotherapy beneficial for patients with FIGO stage IC adult granulosa cell tumor of the ovary?

Adult Granulosa Cell Tumors of the Ovary: A Retrospective Study of 36 FIGO Stage I Cases with Emphasis on Prognostic Pathohistological Features

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