Second-line dovitinib (TKI258) in patients with FGFR2-mutated or FGFR2-non-mutated advanced or metastatic endometrial cancer: a non-randomised, open-label, two-group, two-stage, phase 2 study

Konecny, Gottfried E.; Finkler, Neil J.; García, Agustin A.; Lorusso, Domenica; Lee, Paula S.; Rocconi, Rodney P.; Fong, Peter; Squires, M.; Mishra, Kaushal; Upalawanna, Allison; Wang, Yongyu; Kristeleit, Rebecca

doi:10.1016/s1470-2045(15)70159-2

Cited by 79 publications

(50 citation statements)

References 29 publications

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“…Evidence has linked carcinogenesis and EMT in a range of tissue types with the dysregulation FGFR signaling. It was recently reported that FGFR aberrations were found in 7.1% of cancers [48], while FGFR2 activating mutations were found in 10-16% of primary endometrial cancers [49]. …”

Section: Discussionmentioning

confidence: 99%

Metformin inhibits 17β-estradiol-induced epithelial-to-mesenchymal transition via βKlotho-related ERK1/2 signaling and AMPKα signaling in endometrial adenocarcinoma cells

Liu

Zhao

et al. 2016

Oncotarget

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The potential role of metformin in treating endometrial cancer remains to be explored. The current study investigated the role of metformin in 17β-estradiol-induced epithelial-mesenchymal transition (EMT) in endometrial adenocarcinoma cells. We found that 17β-estradiol promoted proliferation and migration, attenuated apoptosis in both estrogen receptor (ER) positive and ER negative endometrial adenocarcinoma cells (Ishikawa and KLE cells, respectively). Metformin abolished 17β-estradiol-induced cell proliferation and reversed 17β-estradiol-induced EMT in Ishikawa cells. In addition, metformin increased the expression of βKlotho, a fibroblast growth factors (FGFs) coreceptor, and decreased ERK1/2 phosphorylation in both Ishikawa and KLE cells. Decreased expression of βKlotho was noted in human endometrial adenocarcinomas, and plasmid-driven expression of βKlotho in Ishikawa cells abolished 17β-estradiol-induced EMT via inhibiting ERK1/2 signaling. βKlotho expression and metformin show synergetic effects on the proliferation and the EMT in Ishikawa cells. Furthermore, we demonstrated that the anti-EMT effects of metformin could be partly abolished by introducing Compound C, a specific AMPKα signaling inhibitor. In conclusion, metformin abolishes 17β-estradiol-induced cell proliferation and EMT in endometrial adenocarcinoma cells by upregulating βKlotho expression, inhibiting ERK1/2 signaling, and activating AMPKα signaling. Our study provides novel mechanistic insight into the anti-tumor effects of metformin.

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Section: Discussionmentioning

confidence: 99%

Metformin inhibits 17β-estradiol-induced epithelial-to-mesenchymal transition via βKlotho-related ERK1/2 signaling and AMPKα signaling in endometrial adenocarcinoma cells

Liu

Zhao

et al. 2016

Oncotarget

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“…Dovitinib was tested as second-line treatment in urothelial cancer patients classified according to the presence or absence of FGFR3 point mutations, with poor activity regardless of the mutation profile (Milowsky et al, 2014). Recently, this compound has shown no differences in response rate in second-line treatment in metastatic endometrial cancer patients that were classified according to presence or absence of FGFR2 mutations (Konecny et al, 2015). The t (4,14), that affects FGFR3 expression, was considered as selection criteria in a phase II clinical trial in multiple myeloma patients (Chesi et al, 2001).…”

Section: Non-selective Fgfr Tkismentioning

confidence: 99%

FGFR a promising druggable target in cancer: Molecular biology and new drugs

Porta

Borea²,

Coelho³

et al. 2017

Critical Reviews in Oncology/Hematology

168

161

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Introduction The Fibroblast Growth Factor Receptor (FGFR) family consists of Tyrosine Kinase Receptors (TKR) involved in several biological functions. Recently, alterations of FGFR have been reported to be important for progression and development of several cancers. In this setting, different studies are trying to evaluate the efficacy of different therapies targeting FGFR. Areas Covered This review summarizes the current status of treatments targeting FGFR, focusing on the trials that are evaluating the FGFR profile as inclusion criteria: Multi-Target, Pan-FGFR Inhibitors and anti-FGF (Fibroblast Growth Factor)/FGFR Monoclonal Antibodies. Expert opinion Most of the TKR share intracellular signaling pathways; therefore, cancer cells tend to overcome the inhibition of one tyrosine kinase receptor by activating another. The future of TKI (Tyrosine Kinase Inhibitor) therapy will potentially come from multi-targeted TKIs that target different TKR simultaneously. It is crucial to understand the interaction of the FGF-FGFR axis with other known driver TKRs. Based on this, it is possible to develop therapeutic strategies targeting multiple connected TKRs at once. One correct step in this direction is the reassessment of multi target inhibitors considering the FGFR status of the tumor. Another opportunity arises from assessing the use of FGFR TKI on patients harboring FGFR alterations

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“…Beside targeted therapy including combinations with endocrine therapy and CDK4/6 inhibitors or VEGF-(R) inhibitors or FGFR-inhibitors, application of immunotherapy might have strong impact in that stage of disease [104,105].…”

Section: Endometrial Cancersmentioning

confidence: 99%

Immunotherapy in Gynecologic Cancers

Vetter¹,

Heinzelmann‐Schwarz²

2017

Immunotherapy - Myths, Reality, Ideas, Future

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During the last years, significant progress in the understanding of signaling pathways of immune cells has revive the field of immune therapy for cancer. In this chapter, we explain the recent immunotherapy-based strategies for the treatment of gynecological cancers including cervical cancer, endometrial cancer, ovarian cancer, and vulvar cancer. This work will mainly focus on emerging clinical data on immune checkpoint inhibitors. But also data on adoptive T cell therapies and vaccines will be presented. It is anticipated that in future biomarker-guided randomized trials will provide better approaches in terms of response and resistance to immune therapy. The use of combination therapy for gynecological cancer might be one possible approach to overcome resistance.

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Second-line dovitinib (TKI258) in patients with FGFR2-mutated or FGFR2-non-mutated advanced or metastatic endometrial cancer: a non-randomised, open-label, two-group, two-stage, phase 2 study

Cited by 79 publications

References 29 publications

Metformin inhibits 17β-estradiol-induced epithelial-to-mesenchymal transition via βKlotho-related ERK1/2 signaling and AMPKα signaling in endometrial adenocarcinoma cells

Metformin inhibits 17β-estradiol-induced epithelial-to-mesenchymal transition via βKlotho-related ERK1/2 signaling and AMPKα signaling in endometrial adenocarcinoma cells

FGFR a promising druggable target in cancer: Molecular biology and new drugs

Immunotherapy in Gynecologic Cancers

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