Endometrial carcinoma

PTEN-PI3K–AKT pathway

The PI3K–AKT pathway is one of the most frequently abnormal signalling pathways in EEC, often resulting from mutations in the tumour suppressor gene PTEN and activating mutations in PIK3CA.

The importance of the PI3K–PTEN–AKT survival pathway in EC raises the possibility that PI3K inhibitors may be used as potential anticancer agents. In fact, a decrease of AKT phosphorylation and increased apoptosis are seen in mutated PTEN human endometrial cancer cells in the presence of PI3K inhibitor.

It has been shown recently that EC tumours with PTEN mutations have a high level of genetic instability and defects in repair of DNA double-strand breaks by homologous recombination, similar in some ways to that seen for breast and ovarian cancers with alterations in BRCA-1 and BRCA-2.

For this reason, some investigators have suggested using PARP inhibitors in the treatment of patients with PTEN mutated EC.

Of particular interest among AKT targets is the downstream effector mammalian target of rapamycin (mTOR).

AKT activates mTOR via direct phosphorylation of tuberous sclerosis 2 (TCS2) protein and by the inhibition of 5′-AMP-activated protein kinase (AMPPK), thereby activating Rheb (Ras homologue enriched in brain) and mTOR–Raptor activity.

Upon activation, mTOR–Raptor phosphorylates S6K and 4EBP1, resulting in initiation of translation.

The activation of mTORC1 downstream targets leads to protein synthesis, such as cell cycle regulating proteins, vascular endothelial growth factor (VEGF) or c-Myc.

mTOR inhibitors (rapamycin and rapamycin derivatives – also called rapalogues) have been developed recently as potential anticancer agents.

Tumours associated with PTEN inactivation, like EC, are particularly susceptible to the therapeutic effects of mTOR inhibitors.

Several mTOR inhibitors are available for clinical trials: the prototype rapamycin and three rapamycin derivatives, CCI-779 (temsirolimus), RAD001 (everolimus) and AP23573 (ridaforolimus).

PTEN± mice are a good model for testing the sensitivity of EC to anticancer drugs, because they develop complex atypical hyperplasia and endometrial carcinoma.

The use of dual PI3K–mTOR has been proposed as a targeted therapy in EC. The p110 subunits of PI3K and mTOR share similar structures.

Pharmacological inhibitors of p110 may also inhibit mTOR. It has been shown that mTOR inhibitors often lead to feedback activation of PI3K.

Dual PI3K and mTOR inhibitors may inactivate PI3K and mTOR, but also reduce the feedback activation of PI3K caused by mTOR inhibition, thus obtaining increased therapeutic effects.

Considering the high frequency of mutations in both PIK3CA and PTEN in EC, a dual PI3K–mTOR inhibitor, such as BEZ235, would be a promising molecular-targeted therapy in endometrial cancer.

Tyrosine kinase receptors

Tyrosine kinase receptors are also good targets for anticancer therapies. The epidermal growth factor (EGF) receptor family and its growth factors are known to play critical roles in cell growth and differentiation.

Increased expression of EGF-related protein and epidermal growth factor receptor (EGFR) may contribute to a drug-resistant phenotype.

EGFR has intrinsic tyrosine kinase activity which is activated upon ligand binding. Inhibition of EGFR with monoclonal antibodies leads to growth arrest, and a similar and potentially synergistic effect is anticipated with inhibition of EGFR tyrosine kinase activity.

Potential agents are gefitinib, trastuzumab and lapatinib. Erlotinib, an EGF inhibitor, was associated with a response rate of only 13% of EC patients.

Sunitinib is an inhibitor of multiple tyrosine kinase receptors, including c-kit, VEGFR, platelet-derived growth factor receptor (PDGFR) and EGFR. It has also been shown recently that sunitinib targets NF-κB.

Several multi-target kinase inhibitors targeting FGFRs have been also proposed. These receptors mediate signalling from their high-affinity ligands, FGFs. FGF binding leads to FGFR dimerization, followed by receptor autophosphorylation and activation of downstream signalling pathways. These signalling pathways have been shown to contribute to FGFR-mediated cell proliferation and migration.

Mutations in FGFR2 have been described in EC, providing a rationale for targeting FGFR2 to treat patients with refractory tumours. Inhibition of FGFR2 kinase activity in EC cell lines bearing such FGFR2 mutations inhibits transformation and survival. Several agents with activity against FGFRs are currently in clinical trials.

Sorafenib is a potent receptor tyrosine kinase inhibitor with antiproliferative and anti-angiogenic activities that may result in clinical benefit for a minority of EC patients. There is recent evidence showing that sorafenib sensitizes EC cells to TRAIL-induced apoptosis by down-regulating FLIP and Mcl-1.[69]

Bevacizumab, a recombinant humanized immunoglobulin monoclonal antibody to VEGF, has been used in a small series of patients with recurrent EC, with response in 20% and disease stabilization in 30%.

Oestrogen and progesterone

Oestrogen and progesterone are the most important steroid hormones that modulate endometrial cell proliferation and differentiation. Medroxiprogesterone acetate has been studied in EC patients. Interestingly, there is preclinical and clinical evidence that mTOR inhibition may have a synergistic effect on hormonal therapy.

Apoptosis

Apoptosis may be also subjected to targeted therapy. The recent evidence that NF-κB activation is frequent in EC may explain the presence of apoptosis resistance by activation of target genes such as FLIP and Bcl-xL.

Proteasome inhibitors

Proteasome inhibitors are currently used as chemotherapeutic drugs because of their ability to trigger cell growth arrest or apoptosis on several tumours.

In many different types of tumour cells, bortezomib and other proteasome inhibitors cause cell death by blocking NF-κB activity. Interestingly, blockade of NF-κB activity by tyrosine kinase inhibitor sunitinib increases cell death in bortezomib-treated EC cell lines.

Epigenetics

There is increasing evidence that epigenetic alterations contribute to cancer initiation and progression. In contrast to genetic mutations, epigenetic changes are reversible and are therefore an attractive target for cancer therapy.

Histone deacetylase inhibitors (HDACi), such as vorinostat, are a relatively new class of drugs that play important roles in epigenetic or non-epigenetic regulation, inducing death, apoptosis and cell cycle arrest in cancer cells.

Current investigations have suggested that HDACi have antitumour activity against solid tumours.

Credits

 Molecular pathology of endometrial carcinoma. Matias-Guiu X, Prat J. Histopathology. 2013 Jan;62(1):111-23. doi : 10.1111/his.12053 PMID: 23240673

Reviews

 Molecular pathology of endometrial carcinoma. Matias-Guiu X, Prat J. Histopathology. 2013 Jan;62(1):111-23. doi : 10.1111/his.12053 PMID: 23240673

References

 Dedes KJ, Wetterskog D, Mendes-Pereira AM et al. PTEN deficiency in endometrioid endometrial adenocarcinomas predicts sensitivity to PARP inhibitors. Sci. Transl. Med. 2010; 2; 53ra.

 Serra V, Markman B, Scaltriti M et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res. 2008; 68; 8022–8030.

 Shoji K, Oda K, Kashiyama T et al. Genotype-dependent efficacy of a dual PI3K/mTOR inhibitor, NVP-BEZ235, and an mTOR inhibitor, RAD001, in endometrial carcinomas. PLoS ONE 2012; 7; e37431.
CrossRef,CAS,Web of Science®,ADS

 Llobet D, Eritja N, Encinas M et al. The multikinase inhibitor sorafenib induces apoptosis and sensitizes endometrial cancer cells to TRAIL by different mechanisms. Eur. J. Cancer 2010; 46; 836–850.

 Dolcet X, Llobet D, Encinas M et al. Proteasome inhibitors induce death but activate NF-KB on endometrial carcinoma cell lines and primary culture explants. J. Biol. Chem. 2006; 281; 22118–22130.

 Sorolla A, Yeramian A, Valls J et al. Blockade of NFκB activity by Sunitinib increases cell death in Bortezomib-treated endometrial carcinoma cells. Mol. Oncol. 2012; 6; 530–541.