PI3K/AKT/mTOR inhibitors for advanced or recurrent endometrial cancer

Roncolato, Felicia; Lindemann, Kristina; Willson, Melina L; Martyn, Julie; Mileshkin, Linda

doi:10.1002/14651858.cd012160.pub2

Cited by 65 publications

(62 citation statements)

References 39 publications

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“…The PI3K-AKT-mTOR pathway leads to intracellular metabolic changes, involved in metabolic reprogramming such as upregulation of glycolytic enzymes, and disruption of mitochondrial function. Studies targeting PI3K-AKT-mTOR in malignancies have afforded promising results [64][65][66][67], and could be relevant to DN [68]. Accordingly, nephroprotective effects of the old anti-diabetic drug metformin, mediated via the AMPK/mTOR signaling axis, have been recently described, including diminution of apoptosis [69].…”

Section: Discussionmentioning

confidence: 99%

VEGFR2 Blockade Improves Renal Damage in an Experimental Model of Type 2 Diabetic Nephropathy

Lavoz

Rodrigues-Díez

Plaza

et al. 2020

JCM

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The absence of optimal treatments for Diabetic Nephropathy (DN) highlights the importance of the search for novel therapeutic targets. The vascular endothelial growth factor receptor 2 (VEGFR2) pathway is activated in experimental and human DN, but the effects of its blockade in experimental models of DN is still controversial. Here, we test the effects of a therapeutic anti-VEGFR2 treatment, using a VEGFR2 kinase inhibitor, on the progression of renal damage in the BTBR ob/ob (leptin deficiency mutation) mice. This experimental diabetic model develops histological characteristics mimicking the key features of advanced human DN. A VEGFR2 pathway-activation blockade using the VEGFR2 kinase inhibitor SU5416, starting after kidney disease development, improves renal function, glomerular damage (mesangial matrix expansion and basement membrane thickening), tubulointerstitial inflammation and tubular atrophy, compared to untreated diabetic mice. The downstream mechanisms involved in these beneficial effects of VEGFR2 blockade include gene expression restoration of podocyte markers and downregulation of renal injury biomarkers and pro-inflammatory mediators. Several ligands can activate VEGFR2, including the canonical ligands VEGFs and GREMLIN. Activation of a GREMLIN/VEGFR2 pathway, but not other ligands, is correlated with renal damage progression in BTBR ob/ob diabetic mice. RNA sequencing analysis of GREMLIN-regulated genes confirm the modulation of proinflammatory genes and related-molecular pathways. Overall, these data show that a GREMLIN/VEGFR2 pathway activation is involved in diabetic kidney disease and could potentially be a novel therapeutic target in this clinical condition.

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Section: Discussionmentioning

confidence: 99%

VEGFR2 Blockade Improves Renal Damage in an Experimental Model of Type 2 Diabetic Nephropathy

Lavoz

Rodrigues-Díez

Plaza

et al. 2020

JCM

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“…Several compensatory feedback mechanisms have been reported to by guest on October 29, 2020regulate IGF1-R signaling in cancer cells, including epigenetic and/or negative feedback phosphorylation events(70). Molecular characterization of the impact of SRPK1 inhibitors on these established IGF1R feedback responses should provide insight into the link between SRPK1 and EGF/IGF-1 signaling in EC cells.Overexpression of EGFR, IGF1R and activation of AKT signaling frequently occurs in endometrial tumors and is associated with poor overall survival(59,60,71). However, single agent therapies targeting EGFR, IGF1R, or AKT have not shown therapeutic benefit in EC (2).Here, we observed drug synergy combining SRPK1 and EGFR, IGF1R, or AKT inhibitors in serous or endometrioid endometrial cancer cell lines.…”

mentioning

confidence: 69%

Kinome Profiling of Primary Endometrial Tumors Using Multiplexed Inhibitor Beads and Mass Spectrometry Identifies SRPK1 as Candidate Therapeutic Target

Kurimchak¹,

Kumar²,

Herrera-Montávez³

et al. 2020

Molecular & Cellular Proteomics

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Endometrial carcinoma (EC) is the most common gynecologic malignancy in the United States, with limited effective targeted therapies. Endometrial tumors exhibit frequent alterations in protein kinases, yet only a small fraction of the kinome has been therapeutically explored. To identify kinase therapeutic avenues for EC, we profiled the kinome of endometrial tumors and normal endometrial tissues using Multiplexed Inhibitor Beads and Mass Spectrometry (MIB-MS). Our proteomics analysis identified a network of kinases overexpressed in tumors, including Serine/Arginine-Rich Splicing Factor Kinase 1 (SRPK1). Immunohistochemical (IHC) analysis of endometrial tumors confirmed MIB-MS findings and showed SRPK1 protein levels were highly expressed in endometrioid and uterine serous cancer (USC) histological subtypes. Moreover, querying large-scale genomics studies of EC tumors revealed high expression of SRPK1 correlated with poor survival. Loss-of-function studies targeting SRPK1 in an established USC cell line demonstrated SRPK1 was integral for RNA splicing, as well as cell cycle progression and survival under nutrient deficient conditions. Profiling of USC cells identified a compensatory response to SRPK1 inhibition that involved EGFR and the upregulation of IGF1R and downstream AKT signaling. Co-targeting SRPK1 and EGFR or IGF1R synergistically enhanced growth inhibition in serous and endometrioid cell lines, representing a promising combination therapy for EC.

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“…A study of patients with EC observed that PTEN expression is negatively associated with myometrial invasion depth, indicating that PTEN may play an important role of in the development of EC and is potentially a prognostic indicator of EC (62). It has been reported that metformin inhibits Akt expression and stimulates PTEN and IP3 expression via inhibition of the PI3K-Akt signaling pathway (63). This is considered to be an important mechanism via which metformin inhibits the development of EC; both in vitro and in vivo evidence suggest that inhibition of the PI3K-Akt signaling pathway is a key mechanism via which metformin suppresses the carcinogenesis and metastasis of EC (64).…”

Section: Metformin Directly Inhibits the Development Of Ecmentioning

confidence: 99%

“…Furthermore, endometrial hyperplasia has been shown to be reversed by metformin management, with suppression of the PI3K-Akt-mTOR signaling pathway appearing to serve a key role in this inhibitory effect (37). Additionally, it has been suggested that metformin management is an effective preventative strategy for EC (63).…”

Section: Metformin Directly Inhibits the Development Of Ecmentioning

confidence: 99%

Therapeutic effect of metformin in the treatment of endometrial cancer (Review)

Gao

et al. 2020

Oncol Lett

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The present review aims at reviewing the role of metformin in the treatment of endometrial cancer (EC). According to the literature, excessive estrogen levels and insulin resistance are established risk factors of EC. As a traditional insulin sensitizer and newly discovered anticancer agent, metformin directly and indirectly inhibits the development of EC. The direct mechanisms of metformin include inhibition of the LKB1-AMP-activated protein kinase-mTOR, PI3K-Akt and insulin-like growth factor 1-related signaling pathways, which reduces the proliferation and promotes the apoptosis of EC cells. In the indirect mechanism, metformin increases the insulin sensitivity of body tissues and decreases circulating insulin levels. Decreased levels of insulin increase the blood levels of sex hormone binding globulin, which leads to reductions in circulating estrogen and androgens. The aforementioned findings suggest that metformin serves an important role in the treatment of EC. Increased understanding of the mechanism of metformin in EC may provide novel insights into the treatment of this malignancy.

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PI3K/AKT/mTOR inhibitors for advanced or recurrent endometrial cancer

Cited by 65 publications

References 39 publications

VEGFR2 Blockade Improves Renal Damage in an Experimental Model of Type 2 Diabetic Nephropathy

VEGFR2 Blockade Improves Renal Damage in an Experimental Model of Type 2 Diabetic Nephropathy

Kinome Profiling of Primary Endometrial Tumors Using Multiplexed Inhibitor Beads and Mass Spectrometry Identifies SRPK1 as Candidate Therapeutic Target

Therapeutic effect of metformin in the treatment of endometrial cancer (Review)

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