Alterations of Hypoxia-Induced Factor Signaling Pathway Due to Mammalian Target of Rapamycin (mTOR) Suppression in Ovarian Clear Cell Adenocarcinoma: In Vivo and in Vitro Explorations for Clinical Trial

Hirasawa, Takeshi; Miyazawa, Masaki; Yasuda, Masanori; Shida, Masako; Ikeda, Masae; Kajiwara, Hiroshi; Matsui, Naruaki; Fujita, Mariko; Muramatsu, Toshiya; Mikami, Mikio

doi:10.1097/igc.0b013e31829d2d51

Cited by 8 publications

(6 citation statements)

References 25 publications

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“…Anticancer drugs targeting mTOR include everolimus, an mTOR inhibitor used to treat renal cell carcinoma (88). Gene analysis of ovarian cancer tissues revealed mTOR mutations, therefore suggesting the effectiveness of mTOR inhibitors in ovarian cancer (88)(89)(90). In mice with subcutaneously implanted human ovarian clear cell carcinoma cells, the tumor size was halved following treatment with everolimus, Taxol ® and cisplatin (86).…”

Section: Clinical Application Of the Results From Genomic Analysismentioning

confidence: 99%

Genome-wide analysis of gynecologic cancer: The Cancer Genome Atlas in ovarian and endometrial cancer

et al. 2017

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Section: Clinical Application Of the Results From Genomic Analysismentioning

confidence: 99%

Genome-wide analysis of gynecologic cancer: The Cancer Genome Atlas in ovarian and endometrial cancer

et al. 2017

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“…Furthermore, Hirasawa et al compared four groups receiving placebo, everolimus alone, paclitaxel/cisplatin alone, and everolimus + paclitaxel/cisplatin in vivo and reported that antitumor efficacy was highest in the everolimus + paclitaxel/cisplatin group. While tumor growth was inhibited in the group receiving everolimus alone in their report, little cytoreductive effect was obtained 18. Therefore, it may be difficult to obtain an antitumor effect in ovarian clear cell adenocarcinoma with everolimus alone, and we anticipate that an additional effect would be obtained by combining this agent with other anticancer drugs.…”

Section: Discussionmentioning

confidence: 85%

Effective use of everolimus as salvage chemotherapy for ovarian clear cell carcinoma: a case report

Takatori¹,

Shoji²,

Miura³

et al. 2014

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A case study using mammalian target of rapamycin complex 1 in recurrent ovarian clear cell carcinoma (CCC) was recently conducted. We report our experience with a patient suffering from recurrent ovarian CCC who achieved long-term disease control with everolimus administration. The patient was a 53-year-old woman who was diagnosed with recurrent ovarian CCC with dissemination throughout the abdominal cavity. Previously, she had received three chemotherapy regimens, but the disease was progressive and she showed no response to treatment. Therefore, oral everolimus administration (everolimus 10 mg/day on days 1–28, a 28-day period comprised one cycle) was started. She was administered six cycles. The antitumor response was stable disease, and grade 3 anemia was observed. Chemotherapy was then switched to gemcitabine/docetaxel therapy. In the middle of the second cycle, a rapid increase in ascitic fluid and CA125 elevation were observed. Thereafter, the patient received best supportive care and died of the disease. Everolimus may inhibit malignant progression of ovarian CCC.

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“…Therefore, by relieving CIP2A inhibition of PP2A, the PI3K inhibitors would enforce PP2A action in de-phosphorylating target residues on STAT5 thereby resulting in reduced activation. The changes in CIP2A levels in cells exposed to PI3K/mTOR inhibitors were under the control of a microcircuit involving Hif1α [ 55 , 56 ] and its target SNAI1 [ 57 ], and caused enhanced expression of miR-375, a known negative regulator of CIP2A transcription. A schematic representation of this pathway, on the basis of information derived from the literature and original data from this work, is illustrated in Figure 7 .…”

Section: Discussionmentioning

confidence: 99%

Inhibitors of the PI3K/mTOR pathway prevent STAT5 phosphorylation inJAK2V617Fmutated cells through PP2A/CIP2A axis

et al. 2017

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Inhibition of the constitutively activated JAK/STAT pathway in JAK2V617F mutated cells by the JAK1/JAK2 inhibitor ruxolitinib resulted in clinical benefits in patients with myeloproliferative neoplasms. However, evidence of disease-modifying effects remains scanty; furthermore, some patients do not respond adequately to ruxolitinib, or have transient responses, thus novel treatment strategies are needed. Here we demonstrate that ruxolitinib causes incomplete inhibition of STAT5 in JAK2V617F mutated cells due to persistence of phosphorylated serine residues of STAT5b, that conversely are targeted by PI3K and mTORC1 inhibitors. We found that PI3K/mTOR-dependent phosphorylation of STAT5b serine residues involves Protein Phosphatase 2A and its repressor CIP2A. The levels of CIP2A were found increased in cells harboring the JAK2V617F mutation, and we provide evidence of a correlation between clinical responses and the extent of CIP2A downregulation in myelofibrosis patients receiving the mTOR inhibitor RAD001 in a phase II clinical trial. To achieve maximal inhibition of STAT5 phosphorylation, we combined ruxolitinib with BKM120, a PI3K inhibitor, and RAD001, an mTOR inhibitor, obtaining improved efficacy in JAK2V617F mutated cell lines, primary patients’ cells, and JAK2V617F knock-in mice. These findings contribute to understanding the effectiveness of PI3K/mTOR inhibitors in MPN and argue for the rationale to develop combination clinical trials.

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Alterations of Hypoxia-Induced Factor Signaling Pathway Due to Mammalian Target of Rapamycin (mTOR) Suppression in Ovarian Clear Cell Adenocarcinoma: In Vivo and in Vitro Explorations for Clinical Trial

Abstract: Treatment by mTOR inhibitor is expected to down-regulate the cell proliferation of the CCA as a new therapeutic strategy.

Cited by 8 publications

References 25 publications

Genome-wide analysis of gynecologic cancer: The Cancer Genome Atlas in ovarian and endometrial cancer

Genome-wide analysis of gynecologic cancer: The Cancer Genome Atlas in ovarian and endometrial cancer

Effective use of everolimus as salvage chemotherapy for ovarian clear cell carcinoma: a case report

Inhibitors of the PI3K/mTOR pathway prevent STAT5 phosphorylation inJAK2V617Fmutated cells through PP2A/CIP2A axis

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