Tyrosine Kinase Inhibitors as Potential Therapeutic Agents in the Treatment of Granulosa Cell Tumors of the Ovary

Jamieson, Stacey; Fuller, Peter J.

doi:10.1097/igc.0000000000000479

Cited by 13 publications

(14 citation statements)

References 36 publications

(42 reference statements)

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“…Although dasatinib primarily targets SRC and ABL, it also inhibits a variety of other tyrosine kinases, such as PDGFR and ephrin receptors [31]. Consistent with an earlier report of the effects of an SRC inhibitor in KGN cells [32], the present study showed that dasatinib strongly and selectively inhibited AGCT cell viability. Interestingly, dasatinib was effective in FOXL2-mutation positive AGCTs and the KGN cell line, whereas the responses in FOXL2 wild-type COV434 cells and hGL reference cells were significantly weaker.…”

Section: Discussionsupporting

confidence: 91%

Systematic drug sensitivity testing reveals synergistic growth inhibition by dasatinib or mTOR inhibitors with paclitaxel in ovarian granulosa cell tumor cells

Haltia

Andersson

Yadav

et al. 2017

Gynecologic Oncology

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We used a systematic functional approach to reveal novel treatment options for a unique gynecological cancer. The selective synergy found between taxanes and dasatinib or mTOR inhibitors warrants further clinical investigations of these combinations in relapsed or aggressive AGCTs and demonstrate that high-throughput drug screening and molecular profiling can provide an effective approach to uncover new therapy options.

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Section: Discussionsupporting

confidence: 91%

Systematic drug sensitivity testing reveals synergistic growth inhibition by dasatinib or mTOR inhibitors with paclitaxel in ovarian granulosa cell tumor cells

Haltia

Andersson

Yadav

et al. 2017

Gynecologic Oncology

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“…The associations of the mutated genes identified in the pathway analysis (Table 6) may broadly suggest pathways that may be targeted therapeutically. The association with EGFR signaling genes is particularly intriguing given first that the aGCT-derived KGN cell line exhibits constitutive activity of the MAPK pathway (26,27) through mechanisms that remain to be defined, and second that a high frequency of the TERT promoter mutation has been associated with tumor types that exhibit activation of MAPK signaling (6). The functional significance of the copy number changes requires further characterization, although the observed changes have previously been reported not to correlate with tumor stage or behavior (2,(18)(19)(20).…”

Section: Discussionmentioning

confidence: 99%

Mutational Landscape of Ovarian Adult Granulosa Cell Tumors from Whole Exome and Targeted TERT Promoter Sequencing

Alexiadis

Rowley

Chu

et al. 2019

Molecular Cancer Research

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Adult granulosa cell tumor (aGCT), the most common malignant ovarian sex cord-stromal tumor, is characterized by the forkhead transcription factor FOXL2 p.C134W somatic mutation. Late recurrences are relatively common but the molecular mechanisms of relapse or aggressive behavior are not known. The mutational landscape of FOXL2 p.C134W mutation-positive tumors ( = 22) was determined using whole-exome sequencing (WES). An average of 64 coding and essential splice-site variants were identified per tumor. As the TERT promoter region is poorly covered by the WES, targeted sequencing identified the TERT -124C>T promoter mutation as the only recurrent mutation (∼40% of cases). Pathway analysis suggested an association with DNA replication/repair and the EGFR family canonical pathways. Copy number analysis confirmed that gains of chromosomes 12 and 14 occur in approximately 30% of aGCT and loss of chromosome 22 occurs in approximately 40% of cases. In summary, exome-wide analysis of the mutational landscape of aGCT revealed that, except for the TERT promoter mutation, recurrence and/or aggressive behavior is not defined by activation or loss of specific genes. This study found that although aGCTs are defined by the presence of a common gene mutation, recurrence and/or aggressive behavior cannot be attributed to subsequent mutation of specific gene(s) or pathways; however, there is a high frequency of the TERT -124C>T promoter mutation, which is associated with more aggressive disease.

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“…Currently treatment options, once surgery is no longer relevant, are limited [ 1 ]. Although there have been a number of studies which explore the role of various mitogenic signaling pathways in aGCT [ 4 – 7 ] the specific question of what differentiates stage 1 disease from advanced stage disease has not been explored.…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic analysis of stage 1 versus advanced adult granulosa cell tumors

et al. 2016

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Ovarian granulosa cell tumors (GCT) are hormonally-active neoplasms characterized, in the adult-subtype, by a mutation in the FOXL2 gene (C134W). They exhibit an indolent course with an unexplained propensity for late recurrence; ∼80% of patients with aggressive, advanced stage tumors die from their disease; aside from surgery, therapeutic options are limited. To identify the molecular basis of advanced stage disease we have used whole transcriptome analysis of FOXL2 C134W mutation positive adult (a)GCT to identify genes that are differentially expressed between early (stage 1) and advanced (stage 3) aGCT. Transcriptome profiles for early (n = 6) and stage 3 (n = 6) aGCT, and for the aGCT-derived KGN, cell line identified 24 genes whose expression significantly differs between the early and stage 3 aGCT. Of these, 16 were more abundantly expressed in the stage 3 aGCT and 8 were higher in the stage 1 tumors. These changes were further examined for the genes which showed the greatest fold change: the cytokine CXCL14, microfibrillar-associated protein 5, insulin-like 3 and desmin. Gene Set Enrichment Analysis identified overexpression of genes on chromosome 7p15 which includes the homeobox A gene locus. The analysis therefore identifies a small number of genes with clearly discriminate patterns of expression arguing that the clinicopathological-derived distinction of the tumor stage is robust, whilst confirming the relative homogeneity of expression for many genes across the cohort and hence of aGCT. The expression profiles do however identify several overexpressed genes in both stage 1 and/or stage 3 aGCT which warrant further study as possible therapeutic targets.

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Tyrosine Kinase Inhibitors as Potential Therapeutic Agents in the Treatment of Granulosa Cell Tumors of the Ovary

Abstract: These findings implicate BRAF in the activated signaling responsible for the growth and viability of GCT and suggest that TKI already in clinical use may be a therapeutic option in the treatment of GCT.

Cited by 13 publications

References 36 publications

Systematic drug sensitivity testing reveals synergistic growth inhibition by dasatinib or mTOR inhibitors with paclitaxel in ovarian granulosa cell tumor cells

Systematic drug sensitivity testing reveals synergistic growth inhibition by dasatinib or mTOR inhibitors with paclitaxel in ovarian granulosa cell tumor cells

Mutational Landscape of Ovarian Adult Granulosa Cell Tumors from Whole Exome and Targeted TERT Promoter Sequencing

Transcriptomic analysis of stage 1 versus advanced adult granulosa cell tumors

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