Investigational PI3K/AKT/mTOR inhibitors in development for endometrial cancer

Barra, Fabio; Evangelisti, Giulio; Desideri, Lorenzo Ferro; Domenico, Stefano Di; Ferraioli, Domenico; Vellone, Valerio Gaetano; Cian, Franco De; Ferrero, Simone

doi:10.1080/13543784.2018.1558202

Cited by 72 publications

(58 citation statements)

References 93 publications

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“…In recent years, the oncogenic effects of phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling in cancer, including in endometrial carcinoma, have received increasing recognition (14,15). Philip et al reported that inhibition of PI3K/Akt/mTOR signaling increased the sensitivity of endometrial carcinoma cells to some targeted therapies (16).…”

Section: Introductionmentioning

confidence: 99%

CD47 Enhances Cell Viability and Migration Ability but Inhibits Apoptosis in Endometrial Carcinoma Cells via the PI3K/Akt/mTOR Signaling Pathway

et al. 2020

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Purposes: To measure expression levels of CD47 during endometrial carcinoma development, and to determine specific modulatory effects. Methods: CD47 expression levels in endometrial carcinoma tissues and adjacent tissues were analyzed using qRT-PCR. CD47-overexpressed or downregulated cell models were established using CD47 plasmid or CD47 shRNA. The effects of CD47 on HEC-1A and Ishikawa cell growth were evaluated using CCK-8 assays. Migration ability of transfected HEC-1A and Ishikawa cells were examined using wound healing assays. Flow cytometry was used to measure the effects of CD47 on apoptosis and the cell cycle in HEC-1A and Ishikawa cells. Western blot was used to analyze the correlation between CD47 expression level and PI3K/Akt/mTOR signaling pathway. Results: Highly expressed CD47 was observed in endometrial carcinoma tissues, with higher levels in more advanced tissues than in early tissues. Upregulation of CD47 enhanced cell viability and migration ability in HEC-1A and Ishikawa cells, while silencing CD47 caused the opposite results. CD47 overexpression suppressed apoptosis and inhibited cell cycle arrest in HEC-1A and Ishikawa cells. CD47 upregulation contributes to the activation of PI3K/Akt/mTOR signaling pathway in endometrial carcinoma cells. Conclusion: CD47 exerts oncogenic functions in endometrial carcinoma by activating PI3K/Akt/mTOR signaling, suggesting it may be a novel immunotherapeutic target for therapeutic interventions.

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Section: Introductionmentioning

confidence: 99%

CD47 Enhances Cell Viability and Migration Ability but Inhibits Apoptosis in Endometrial Carcinoma Cells via the PI3K/Akt/mTOR Signaling Pathway

et al. 2020

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“…Inhibition of PI3K/AKT/mTOR signaling strongly suppresses EEC progression (36)(37)(38) and clinical trials targeting PI3K/AKT/mTOR signaling in solid tumors have shown promise (39). However, the bene ts of this against in endometrial cancers is controversial due to the complexity of pharmacological action and toxicity (40). Further studies are needed to better target PI3K/AKT/mTOR signaling in endometrial cancer.…”

Section: Discussionmentioning

confidence: 99%

A 4-gene Signature Predicts Prognosis of Uterine Serous Carcinoma

Chen

Qin

Xiong

et al. 2020

Preprint

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Background: Uterine serous carcinoma (USC) is a rare, aggressive variant of endometrial cancer that accounts for more than 50% of endometrial cancer deaths, creating an urgent need for prognostic biomarkers. Methods: USC RNA-Seq data and corresponding patients’ clinical records were obtained from The Cancer Genome Atlas and Genotype-Tissue Expression datasets. Univariate cox, Lasso, and Multivariate cox regression analyses were conducted to forge a prognostic signature. Multivariable and univariable cox regression analysis and ROC curve evaluated the prediction efficiency both in the training and testing sets. Results: We uncovered 1385 genes dysregulated in 110 cases of USC tissue relative to 113 cases of normal uterine tissue. Functional enrichment analysis of these genes revealed the involvement of various cancer-related pathways in USC. A novel 4‐gene signature (KRT23, CXCL1, SOX9 and ABCA10) of USC prognosis was finally forged by serial regression analyses. Overall patient survival (OS) and recurrence-free survival (RFS) were significantly lower in the high-risk group relative to the low-risk group in both the training and testing sets. The area under the ROC curve of the 4-gene signature was highest among clinicopathological features in predicting OS and RFS. The 4-gene signature was found to be an independent prognostic indicator in USC and was a superior predictor of OS in early stage of USC. Conclusions: Our findings highlight the potential of the 4-gene signature as a guide for personalized USC treatment.

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“…Among solid tumours, EC presents the highest alteration rate of the PI3K/AKT/mTOR pathway, being altered specifically in 92% of type I and 60% of type II ECs [ 3 ]. Usually, PI3K/AKT/mTOR pathway overactivation occurs as a result of overexpression of upstream tyrosine kinase growth factor receptors, phosphatase and tensin homolog (PTEN)loss-of-function (mutated in 67–84% of EC type I and 3–22% of EC type II), amplification or mutation in PI3KCA (38–55% of EC type I and 10–47% of EC type II), PIK3R1 (21–43% of EC type I and 12–17 of % of EC type II), and AKT genes (2% of EC type I) and elevated expression of mTOR (7% of EC type I) [ 8 , 9 ]. Overall, these data underline that the PI3K/AKT/mTOR pathway has a crucial role in EC pathogenesis, despite the slight differences in the frequency and types of alterations found in the two main histological tumour types.…”

Section: Small-molecule Inhibitors For Endometrial Cancer Therapymentioning

confidence: 99%

“…These small inhibitors can suppress both the mTORC1 and mTORC2 and their main advantage is the considerable decrease of AKT phosphorylation and better inhibition of mTORC1. Those inhibitors are developed to have an increased therapeutic effect and less resistance [ 9 ]. Preclinical studies analysing the effect of second-generation mTOR inhibitors, such as Vistusertib (AZD2014) and AZD8055, have resulted in dose-dependent growth inhibition and apoptosis in a variety of EC cell lines [ 24 , 25 ].…”

Section: Small-molecule Inhibitors For Endometrial Cancer Therapymentioning

confidence: 99%

Small-Molecule Inhibitors (SMIs) as an Effective Therapeutic Strategy for Endometrial Cancer

Megino‐Luque

Moiola

Molins-Escuder

et al. 2020

Cancers

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Endometrial cancer (EC) is the sixth most common cancer in women. A continued number of low-risk EC patients at diagnosis, as well as patients diagnosed with advanced-stage disease, will experience an aggressive disease. Unfortunately, those patients will present recurrence or overt dissemination. Systemic cytotoxic chemotherapy treatment on advanced, recurrent, or metastatic EC patients has shown poor results, with median survival rates of less than one year, and median progression-free survival rates of four months. Therefore, the search for innovative and alternative drugs or the development of combinatorial therapies involving new targeted drugs and standard regimens is imperative. Over the last few decades, some small-molecule inhibitors have been introduced in the clinics for cancer treatment, but only a few have been approved by the Food and Drug Administration (FDA) for EC treatment. In the present review, we present the current state and future prospects of small-molecule inhibitors on EC treatment, both alone and in combination.

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Investigational PI3K/AKT/mTOR inhibitors in development for endometrial cancer

Cited by 72 publications

References 93 publications

CD47 Enhances Cell Viability and Migration Ability but Inhibits Apoptosis in Endometrial Carcinoma Cells via the PI3K/Akt/mTOR Signaling Pathway

CD47 Enhances Cell Viability and Migration Ability but Inhibits Apoptosis in Endometrial Carcinoma Cells via the PI3K/Akt/mTOR Signaling Pathway

A 4-gene Signature Predicts Prognosis of Uterine Serous Carcinoma

Small-Molecule Inhibitors (SMIs) as an Effective Therapeutic Strategy for Endometrial Cancer

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