Genetic and epigenetic heterogeneity of epithelial ovarian cancer and the clinical implications for molecular targeted therapy

Bai, Huimin; Cao, Dongyan; Yang, Jiaxin; Li, Menghui; Zhang, Zhenyu; Shen, Keng

doi:10.1111/jcmm.12771

Cited by 41 publications

(33 citation statements)

References 130 publications

(207 reference statements)

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“…Recent attention has shifted toward targeted therapies for EOC that increase tumor selectivity, while decreasing systemic toxicity (2, 4, 5). Of particular interest are therapies targeting folate receptor (FR) α (6).…”

Section: Introductionmentioning

confidence: 99%

Dual Targeting of Epithelial Ovarian Cancer Via Folate Receptor α and the Proton-Coupled Folate Transporter with 6-Substituted Pyrrolo[2,3-d]pyrimidine Antifolates

Hou

Gattoc

O’Connor

et al. 2017

Molecular Cancer Therapeutics

128

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Folate uptake in epithelial ovarian cancer (EOC) involves the reduced folate carrier (RFC) and the proton-coupled folate transporter (PCFT), both facilitative transporters, and folate receptor (FR) α. Whereas in primary EOC specimens, FRα is widely expressed and increases with tumor stage, PCFT was expressed independent of tumor stage (by real-time RT-PCR and immunohistochemistry). EOC cell line models, including cisplatin sensitive (IGROV1 and A2780) and resistant (SKOV3 and TOV112D) cells, expressed a 17-fold range of FRα and similar amounts (within ∼2-fold) of PCFT. Novel 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolates AGF94 and AGF154 exhibited potent anti-proliferative activities toward all of the EOC cell lines, reflecting selective cellular uptake by FRα and/or PCFT over RFC. When IGROV1 cells were pretreated with AGF94 at pH 6.8, clonogenicity was potently inhibited, confirming cell killing. FRα was knocked down in IGROV1 cells with lentiviral shRNAs. Two FRα knockdown clones (KD-4 and KD-10) showed markedly reduced binding and uptake of [3H]folic acid and [3H]AGF154 by FRα, but maintained high levels of [3H]AGF154 uptake by PCFT compared to non-targeted control cells. In proliferation assays, KD-4 and KD-10 cells preserved in vitro inhibition by AGF94 and AGF154, compared to a non-targeted control, attributable to residual FRα- and substantial PCFT-mediated uptake. KD-10 tumor xenografts in severe-compromised immune deficient mice were likewise sensitive to AGF94. Collectively, our results demonstrate the substantial therapeutic potential of novel 6-substituted pyrrolo[2,3-d]pyrimidine antifolates with dual targeting of PCFT and FRα toward EOCs that express a range of FRα, along with PCFT, as well as cisplatin resistance.

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Section: Introductionmentioning

confidence: 99%

Dual Targeting of Epithelial Ovarian Cancer Via Folate Receptor α and the Proton-Coupled Folate Transporter with 6-Substituted Pyrrolo[2,3-d]pyrimidine Antifolates

Hou

Gattoc

O’Connor

et al. 2017

Molecular Cancer Therapeutics

128

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“…In addition, the major functionality of PcG proteins itself, histone modifications, could serve as valuable epigenetic markers for clinical application. In ovarian cancer, decreased expression of polycomb repressive complex-mediated H3K27me3 is significantly associated with high grade and advanced stage, and can predict resistance to chemotherapy as well 49. However, the relationship between BMI1-participant H2AK119ub1 and clinical outcome in EOC is unclear.…”

Section: Future Challengesmentioning

confidence: 99%

B-cell-specific Moloney murine leukemia virus integration site 1: potential stratification factor and therapeutic target for epithelial ovarian cancer

Zhao

Gui

Qian³

et al. 2016

OTT

Self Cite

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Epithelial ovarian cancer, a vexing challenge for clinical management, still lacks biomarkers for early diagnosis, precise stratification, and prognostic evaluation of patients. B-cell-specific Moloney murine leukemia virus integration site 1 (BMI1), a member of the polycomb group of proteins, engages in diverse cellular processes, including proliferation, differentiation, senescence, and stem cell renewal. In addition, BMI1, as a cancer stem-cell marker, participates in tumorigenesis through various pathways. Rewardingly, recent studies have also revealed a relationship between BMI1 expression and the clinical grade/stage, therapy response, and survival outcome in a majority of human malignancies, including epithelial ovarian cancer. Therefore, BMI1 might serve as a potential stratification factor and treatment target for epithelial ovarian cancer, pending evidence from further investigations.

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“…Aberrant DNA CpG island methylation within genes' promoter region represents one possible mechanism of gene silencing by cancer [20]. The promoter methylation is related to reduction of DIRAS3 expression in most ovarian cancer and breast cancer cells [8,21].…”

Section: Discussionmentioning

confidence: 99%

DNA methyltransferase inhibitors influence on the DIRAS3 and STAT3 expression and in vitro migration of ovarian and breast cancer cells

et al. 2017

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Objectives: Downregulation of DIRAS3 (DIRAS family, GTP-binding Ras-like 3) is related to ovarian and breast cancer progression. A possible mechanism that silences this gene is the promoter region DNA methylation. The potential reversibility of this epigenetic mechanism makes it more attractive candidate for new mode of cancer treatment. DIRAS3 regulates cell cycle, tumor dormancy and inhibits cancer cell growth and motility, all of which may indirectly depend on interaction with STAT3 (Signal Transducer and Activator of Transcription 3) classified as a potential oncogene. The restoration of DIRAS3 expression could inhibit cell proliferation and invasiveness. Material and methods:Human ovarian carcinoma cell line (A2780) and human breast cancer cell line (MCF7) were exposed to two DNA methyltransferase inhibitors (DNMTi): decitabine (5-aza-2'-deoxycytidine) [25 μM and 12.5 μM] and RG108 [150 μM and 100 μM]. In vitro migration changes of cancer cells were examined with wound healing assay. After 7 days of DNMTi treatment cells were harvested and DNA and RNA was isolated. The methylation status of the promoter sequences of DIRAS3 and STAT3 genes was determined using methylation specific PCR (MS-PCR). Level of target genes' expression was quantified using quantitative reverse transcription PCR (QRT-PCR). Results and conclusions:The in vitro wound healing assay showed changes in the migration rate of both adherent cell lines after DNMTi treatment compared to the untreated cells. Relative balance between methylated and unmethylated variants of DIRAS3 after MS-PCR was shifted towards unmethylated version after DNMTi treatment in A2780 cells. Statistically significant dose dependent effect of decitabine and RG108 on DIRAS3 expression in A2780 cells was observed.

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Genetic and epigenetic heterogeneity of epithelial ovarian cancer and the clinical implications for molecular targeted therapy

Cited by 41 publications

References 130 publications

Dual Targeting of Epithelial Ovarian Cancer Via Folate Receptor α and the Proton-Coupled Folate Transporter with 6-Substituted Pyrrolo[2,3-d]pyrimidine Antifolates

Dual Targeting of Epithelial Ovarian Cancer Via Folate Receptor α and the Proton-Coupled Folate Transporter with 6-Substituted Pyrrolo[2,3-d]pyrimidine Antifolates

B-cell-specific Moloney murine leukemia virus integration site 1: potential stratification factor and therapeutic target for epithelial ovarian cancer

DNA methyltransferase inhibitors influence on the DIRAS3 and STAT3 expression and in vitro migration of ovarian and breast cancer cells

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