Emerging therapeutic biomarkers in endometrial cancer

Abstract

Although clinical trials of molecular therapies targeting critical biomarkers (mTOR, epidermal growth factor receptor/epidermal growth factor receptor 2, and vascular endothelial growth factor) in endometrial cancer show modest effects, there are still challenges that might remain regarding primary/acquired drug resistance and unexpected side effects on normal tissues. New studies that aim to target both genetic and epigenetic alterations (noncoding microRNA) underlying malignant properties of tumor cells and to specifically attack tumor cells using cell surface markers overexpressed in tumor tissue are emerging. More importantly, strategies that disrupt the cancer stem cell/epithelial-mesenchymal transition-dependent signals and reactivate antitumor immune responses would bring new hope for complete elimination of all cell compartments in endometrial cancer. We briefly review the current status of molecular therapies tested in clinical trials and mainly discuss the potential therapeutic candidates that are possibly used to develop more effective and specific therapies against endometrial cancer progression and metastasis.

Figure 1

Therapeutic molecular targets for endometrial cancer. Type I endometrial cancer (EC) frequently exhibits altered PI3K/PTEN/AKT/mTOR signal pathway, whereas type II EC frequently shows mutations in p53 and HER-2 overexpression. The upregulation of EGFR and VEGF, dysregulated microRNAs, and activation of cancer stem cell (CSC)/epithelial-mesenchymal transition (EMT) programs are involved in oncogenesis and progression of both cancer types. Currently, clinical trials assessing the efficacy of mTOR inhibitor, EGFR/HER2 inhibitor, and antiangiogenic agent for EC have been conducted and demonstrated modest effects.

Figure 2

Challenges in the molecular therapeutics of human tumor. The clinical success of targeted drugs has been limited by key challenges, including primary/acquired drug resistance and unexpected side effects on normal tissues due to nonspecificity. The most frequent mechanisms of primary resistance are genetic/epigenetic heterogeneity and the existence of cancer stem cell. Acquired resistance can be caused by the secondary mutation in the target gene, activation of alternative pathway or feedback loop, and induction of EMT. Treatment of tumor cells with antiangiogenic agents can lead to a more hypoxic tumor microenvironment and enhance tumor cell invasion and metastasis by inducing the EMT- and cancer-stem-cell-like phenotype.

Figure 3

Potential miRNA-based therapies in EC. The use of antibodies against cell surface markers overexpressed in EC tissue might deliver targeted drugs to EC cells more specifically with fewer side effects on normal tissue. The nanotechnology can be used to develop a more effective delivery system for targeted agents, especially miRNA that might simultaneously modulate multiple signal pathways necessary for malignant phenotype of EC.

Figure 4

Targeting the CSC/EMT signaling pathways in EC. Tumor cells that undergo EMT not only increase their invasion ability, but also concurrently acquire cancer stem cell (CSC) properties. On the other hand, CSCs are associated with enhanced capacity to metastasize. At a molecular level, several signaling pathways involved in the self-renewal of CSCs, including Wnt/β-catenin, Hedgehog, and Notch signaling, can also induce EMT programs. Specific inhibitors targeting these CSC and EMT pathways efficiently suppress the malignant phenotype of EC cells. Other potential therapeutic candidates for EC treatment include Stattic (inhibitor of STAT3), Rapamycin (mTOR inhibitor), and CD133.

Figure 5

Targeting immunosuppressive molecular pathways in EC. Tumor cell induces immunosuppression by the production of immunosuppressive factors such as TGF-β, IL-10, VEGF, and COX-2. Tumor cells undergoing EMT can acquire both aggressive and immunosuppressive properties. Wnt/β-catenin pathway and STAT3-related pathway are activated in tumor cells and immunosuppressive cells and therefore they seem to be attractive targets for EC immunotherapy.