Open-label phase II clinical trial of ketoconazole as CYP17 inhibitor in metastatic or advanced non-resectable granulosa cell ovarian tumors: the GREKO (GRanulosa Et KetOconazole) trial, GETHI 2011-03

García-Donás, Jesús; Hurtado, Alicia; Garrigós, Laia; Santaballa, Ana; Redondo, Andrés; Vidal, Laura; Laínez, Núria; Guerra, Eva; Rodríguez, Víctor M.; Cueva, Juan; Bover, Isabel; Palacio, Isabel; Rubio, María Jesús; Prieto, Mario; Löpez‐Guerrero, José Antonio; Rodriguez-Moreno, Juan Francisco; García-Casado, Zaida; García‐Martínez, Elena; Taus, Alvaro; Castro, Ignacio Pérez de; Navarro, Paloma; Grande, Enrique

doi:10.1007/s12094-023-03085-w

Cited by 3 publications

(2 citation statements)

References 25 publications

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“…On the other hand, inhibition of CYP17 has been proposed as a promising therapeutic option for AGCT [12] because FOXL2 c.402C>G mutation leads to overexpression of this key regulator of steroidogenesis [45]. In fact, Ketoconazole, a CYP17 inhibitor, has shown activity in advanced AGCT in clinical and in vitro studies [35]. Therefore, we decided to study the activity of these two compounds in a contest of CRISPR-mediated elimination of the FOXL2 c.402C>G mutation.…”

Section: Resultsmentioning

confidence: 99%

“…Drug reconstitution and dilution were carried out following datasheet instructions. Drug eligibility was based on previous published works [12,34,35] and Cmap (Connectivity Map, Broad Institute) results derived from our transcriptomic and proteomic studies. Data of differentially expressed genes (DEGs) with a +/-1.5 log2 foldchange and a padj<0.05 and differentialy expressed proteins (DEPs) with a +/-1.25 log2 foldchange and a padj<0.05 were compared and the resulting common genes were then inputted into the Cmap platform for further analysis.…”

Section: Cell Growth Senescence Cell Cycle Migration and Drug Sensiti...mentioning

confidence: 99%

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CRISPR targeting of FOXL2 c.402C>G mutation reduces malignant phenotype in granulosa tumor cells and identifies anti-tumoral compounds

Amarilla-Quintana,

Navarro,

Ramos

et al. 2024

Preprint

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FOXL2 is a transcription factor essential for sex determination and ovary development and maintenance. Mutations in this gene are implicated in syndromes involving premature ovarian failure and granulosa cell tumors (GCTs). This rare cancer accounts for less than 5% of diagnosed ovarian cancers and is causally associated with the FOXL2 c.402C>G, p.C134W mutation in 97% of the adult cases (AGCTs). In this study, we employed CRISPR technology to specifically eliminate the FOXL2 c.402C>G mutation in granulosa tumor cells. Our results show that this Cas9-mediated strategy selectively targets the mutation without affecting the wild-type allele. Granulosa cells lacking the FOXL2 c.402C>G exhibit a reduced malignant phenotype, with significant changes in cell proliferation, invasion, and cell death. Furthermore, these modified cells are more susceptible to Dasatinib and Ketoconazole. Transcriptomic and proteomic analyses reveal that CRISPR-modified granulosa tumor cells shift their expression profiles towards a wild-type like phenotype. Additionally, this altered expression signature has led to the identification of new compounds with antiproliferative and pro-apoptotic effects on granulosa tumor cells. Our findings demonstrate the potential of CRISPR technology for the specific targeting and elimination of a mutation causing granulosa cell tumors, highlighting its therapeutic promise for treating this rare ovarian cancer.Simple SummaryAdult granulosa cell tumors (AGCTs), characterized by a specific point mutation (C134W) in the gene FOXL2, are less than 5% of all the diagnosed ovarian cancers. Surgery is the cornerstone treatment for AGCT even at relapse, with systemic therapy showing poor results. The aim of our study is to explore the potential therapeutic effect of the elimination of the C134W mutation. To achieve our goal, we have eliminated the mutant allele using CRISPR technology. Our results demonstrate that CRISPR-mediated elimination of FOXL2-C134W reduces the malignant phenotype of granulosa tumor cells, which change their transcriptional, proteomic, and cellular phenotype to a wild type like, granulosa type. Moreover, the induced changes allowed us to find new compounds with antitumoral activity. This work highlights the therapeutic potential of CRISPR mediated technology for the treatment of AGCT.

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Section: Resultsmentioning

confidence: 99%

Section: Cell Growth Senescence Cell Cycle Migration and Drug Sensiti...mentioning

confidence: 99%

CRISPR targeting of FOXL2 c.402C>G mutation reduces malignant phenotype in granulosa tumor cells and identifies anti-tumoral compounds

Amarilla-Quintana,

Navarro,

Ramos

et al. 2024

Preprint

Self Cite

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Androgen receptor expression in recurrent granulosa cell tumor of the ovary: Clinical considerations of treatment and surveillance in a transgender male

Tumas,

Alberto Hiraldo,

Berman

2024

Gynecologic Oncology Reports

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Clinicopathologic Characteristics of a Single-institution Cohort of Ovarian Adult Granulosa Cell Tumors, With Biomarker and Therapeutic Implications Utilizing the Detection of Androgen, Estrogen, and Progesterone Hormone Receptor Expression by Immunohistochemistry

Moh,

Puzyrenko,

Summey

et al. 2024

International Journal of Gynecological Pathology

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Adult granulosa cell tumors (AGCTs) are rare ovarian tumors with generally good prognosis after surgical resection; however, they do have recurrence potential. Therapeutic and management options for recurrences are currently limited, and the need for expanded adjuvant therapies is increasingly recognized. Anti-hormonal therapy is being explored as an option, which relies on the detection and assessment of hormone receptor expression (androgen, estrogen, and progesterone receptors) as a biomarker and therapeutic target. Our study identifies several clinicopathologic characteristics with significant associations for recurrence of AGCT, which were younger age, higher stage, and larger tumor size. Our study also demonstrates that androgen receptor (AR) expression may be utilized as a potential biomarker for hormonal therapy and that detection of AR expression in AGCT by immunohistochemistry (IHC) varies depending on the antibody clone used for testing. AR was detected in 95% of samples tested with antibodies derived from clone AR27. This detection rate is much higher than previously reported.

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Open-label phase II clinical trial of ketoconazole as CYP17 inhibitor in metastatic or advanced non-resectable granulosa cell ovarian tumors: the GREKO (GRanulosa Et KetOconazole) trial, GETHI 2011-03

Cited by 3 publications

References 25 publications

CRISPR targeting of FOXL2 c.402C>G mutation reduces malignant phenotype in granulosa tumor cells and identifies anti-tumoral compounds

CRISPR targeting of FOXL2 c.402C>G mutation reduces malignant phenotype in granulosa tumor cells and identifies anti-tumoral compounds

Androgen receptor expression in recurrent granulosa cell tumor of the ovary: Clinical considerations of treatment and surveillance in a transgender male

Clinicopathologic Characteristics of a Single-institution Cohort of Ovarian Adult Granulosa Cell Tumors, With Biomarker and Therapeutic Implications Utilizing the Detection of Androgen, Estrogen, and Progesterone Hormone Receptor Expression by Immunohistochemistry

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