GDC-0941 Inhibits Metastatic Characteristics of Thyroid Carcinomas by Targeting both the Phosphoinositide-3 Kinase (PI3K) and Hypoxia-Inducible Factor-1α (HIF-1α) Pathways

Burrows, Natalie; Babur, Muhammad; Resch, Julia; Ridsdale, Sophie; Mejin, Melissa; Rowling, Emily J.; Brabant, Georg; Williams, Kaye J.

doi:10.1210/jc.2011-1426

Cited by 58 publications

(50 citation statements)

References 26 publications

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“…HIF1 induces expression of VEGF, a growth factor, and MET, an oncogene, which are also upregulated in thyroid tumors as compared to normal thyroid tissues [162]. On the other hand, PI3K-AKT and MAPK increase expression of HIF1 in thyroid tumor [161,164,165] while a mutation in BRAF (V600E) also affects expression levels of HIF1␣ in papillary thyroid cancer [165]. Interestingly, inhibition of expression levels of HIF-1␣ and HIF-2␣ by GDC-0941 in four different thyroid tumor cells (BcPAP, WRO, FTC133, and 8505c) resulted in inhibition of VEGF secretion [166].…”

Section: The Hif1α Pathwaymentioning

confidence: 99%

“…On the other hand, PI3K-AKT and MAPK increase expression of HIF1 in thyroid tumor [161,164,165] while a mutation in BRAF (V600E) also affects expression levels of HIF1␣ in papillary thyroid cancer [165]. Interestingly, inhibition of expression levels of HIF-1␣ and HIF-2␣ by GDC-0941 in four different thyroid tumor cells (BcPAP, WRO, FTC133, and 8505c) resulted in inhibition of VEGF secretion [166]. Koperek et al demonstrated that tumor hypoxia is involved in the development of regional metastases in MTC [167].…”

Section: The Hif1α Pathwaymentioning

confidence: 99%

“…Downstream signaling relay molecules such as BRAF, AKT, MEK and mTOR are examples of therapeutic targets that are being actively tested for the treatment of thyroid cancer [27]. In a recent study, the activity of the PI3K inhibitor GDC-0941 was assessed on hypoxiainducible-factor-1 (HIF-1), a transcription factor regulated by PI3K, for its metastatic behavior of thyroid cancer cells both in vitro and in vivo [164]. GDC-0941 has been shown to inhibit HIF-1␣ and HIF-2␣ expression, and HIF activity in thyroid carcinoma cells.…”

Section: Targeting Pi3kmentioning

confidence: 99%

See 2 more Smart Citations

An update on molecular biology of thyroid cancers

Ömür

Baran

2014

Critical Reviews in Oncology/Hematology

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Section: The Hif1α Pathwaymentioning

confidence: 99%

Section: The Hif1α Pathwaymentioning

confidence: 99%

Section: Targeting Pi3kmentioning

confidence: 99%

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An update on molecular biology of thyroid cancers

Ömür

Baran

2014

Critical Reviews in Oncology/Hematology

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“…The mechanism of this inhibition is solely dependent upon the hypoxia-inducible factor-1α (HIF-1α). It has also been suggested that the anti-proliferative effects of GDC-0941 depend on PTEN status in thyroid cancer [72] , but the mechanism is still unclear. Thus, the role of PTEN status in the effectiveness of GDC-0941 is distinct for different cancer types.…”

Section: Achievements In Clinical Trialsmentioning

confidence: 99%

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

2012

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The PI3K-Akt pathway is a vital regulator of cell proliferation and survival. Alterations in the PIK3CA gene that lead to enhanced PI3K kinase activity have been reported in many human cancer types, including cancers of the colon, breast, brain, liver, stomach and lung. Deregulation of PI3K causes aberrant Akt activity. Therefore targeting this pathway could have implications for cancer treatment. The first generation PI3K-Akt inhibitors were proven to be highly effective with a low IC 50 , but later, they were shown to have toxic side effects and poor pharmacological properties and selectivity. Thus, these inhibitors were only effective in preclinical models. However, derivatives of these first generation inhibitors are much more selective and are quite effective in targeting the PI3K-Akt pathway, either alone or in combination. These second-generation inhibitors are essentially a specific chemical moiety that helps to form a strong hydrogen bond interaction with the PI3K/Akt molecule. The goal of this review is to delineate the current efforts that have been undertaken to inhibit the various components of the PI3K and Akt pathway in different types of cancer both in vitro and in vivo. Our focus here is on these novel therapies and their inhibitory effects that depend upon their chemical nature, as well as their development towards clinical trials.

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“…A second positive regulatory pathway has been described for PI3K/mTOR that is involved in regulating Hif-1 protein synthesis through AKT/PKB (protein kinase B), mTOR (mammalian target of rapamycin) and S6K (p70 S6 kinase) [448]. It has recently been demonstrated that the PI3K inhibitor GDC-0941 represses Hif1 and Hif-2 expression and activity [449].…”

Section: The -Catenin Tcf/lef Transcription Complexmentioning

confidence: 99%

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Voronkov¹,

Krauß²

2012

CPD

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Wnt/ -catenin signaling is a branch of a functional network that dates back to the first metazoans and it is involved in a broad range of biological systems including stem cells, embryonic development and adult organs. Deregulation of components involved in Wnt/ -catenin signaling has been implicated in a wide spectrum of diseases including a number of cancers and degenerative diseases. The key mediator of Wnt signaling, -catenin, serves several cellular functions. It functions in a dynamic mode at multiple cellular locations, including the plasma membrane, where -catenin contributes to the stabilization of intercellular adhesive complexes, the cytoplasm where -catenin levels are regulated and the nucleus where -catenin is involved in transcriptional regulation and chromatin interactions. Central effectors of -catenin levels are a family of cysteine-rich secreted glycoproteins, known as Wnt morphogens. Through the LRP5/6-Frizzled receptor complex, Wnts regulate the location and activity of the destruction complex and consequently intracellularcatenin levels. However, -catenin levels and their effects on transcriptional programs are also influenced by multiple other factors including hypoxia, inflammation, hepatocyte growth factor-mediated signaling, and the cell adhesion molecule E-cadherin. The broad implications of Wnt/ -catenin signaling in development, in the adult body and in disease render the pathway a prime target for pharmacological research and development. The intricate regulation of -catenin at its various locations provides alternative points for therapeutic interventions.

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GDC-0941 Inhibits Metastatic Characteristics of Thyroid Carcinomas by Targeting both the Phosphoinositide-3 Kinase (PI3K) and Hypoxia-Inducible Factor-1α (HIF-1α) Pathways

Abstract: PI3K plays a prominent role in the metastatic behavior of thyroid carcinoma cells irrespective of O(2) tension and appears upstream of HIF activation. GDC-0941 significantly inhibited the metastatic phenotype, supporting the clinical development of PI3K inhibition in thyroid carcinomas.

Cited by 58 publications

References 26 publications

An update on molecular biology of thyroid cancers

An update on molecular biology of thyroid cancers

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

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