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  • The role of the cyclic AMP regulated

    2021-10-12

    The role of the cyclic AMP regulated exchange factor Epac1 is emerging in cancer (Almahariq et al., 2015, Banerjee and Cheng, 2015, Parnell et al., 2015, Parnell et al., 2015, Schmidt et al., 2013). Interestingly, in cancer cell migration, activation of Epac1 can be linked to activation of Rac. As such, Epac1 could prove to be an interesting target for the treatment of cancer metastasis. Considerable interest has recently been given to the development of inhibitors of Epac1. By high-throughput screening for Epac antagonists, the Cheng and colleagues identified several novel Epac subtype-specific inhibitors (Almahariq et al., 2013, Chen et al., 2012, Tsalkova et al., 2012, Tsalkova et al., 2012). Especially the ESI-09, which inhibits both Epac subtypes, has high bioavailability and no toxicity when administered in vivo to mice (Almahariq et al., 2015, Almahariq et al., 2015, Gong et al., 2013, Yan et al., 2013, Zhu et al., 2015). Another Epac antagonist, CE3F4, shows high selectivity for Epac1 compared to Epac2 (Courilleau et al., 2012, Courilleau et al., 2013). The development of more specific Epac subtype inhibitors is currently underway (Wang et al., 2017). Observations from our group show that this inhibitor attenuates PGE2-induced EMT and migration of NSCLC Omeprazole in a β-catenin-dependent manner (Jansen et al., 2016). Thus, the notion put forward earlier that Rho proteins, Epac1 and β-catenin cooperate in driving carcinoma cell migration might be a therapeutically targetable interaction that could decrease dissemination of malignant cells. While further investigation is required to better understand the role of Epac1 in cancer cell migration, both in vitro and in vivo, there is substantial evidence suggesting that Epac1 inhibitors might provide a novel approach for the treatment of cancer metastasis (Almahariq, Mei, et al., 2015). This summary of available strategies to target Rho protein networks on several levels, demonstrates that considerable efforts are underway to develop novel tools that greatly support research on Rho proteins in the context of cell migration and cancer metastasis and asre as such of undeniable value. However, condidering the importance of these signaling pathways in cancer, a surprisingly low number of these compounds have been developed beyond an early preclinical stage. Poor pharmacokinetics and target specificity, as well as the often very context dependent and ambivalent findings, are seriously limiting chances to develop these tools into a clinical setting. Here, we have highlighted how changes in Rho protein networks often result in changes in cell-cell-contacts and cell-ECM contacts and, thereby, in perceived cellular force. These changes often result in abrogated activation and localization of secondary signaling intermediates that have the ability to affect transcriptional programs, thereby translating short-term changes in cellular dynamics in long-lasting effects and as such could be interesting therapeutic targets in cancer. Two of these intermediates have gained a lot of attention over the past decade, namely β-catenin (Clevers & Nusse, 2012) and YAP (Moroishi et al., 2015, Zanconato et al., 2016). Of the plenty of the pharmacological tools inhibiting β-catenin interacting with TCF or other transcriptional co-activators, one made it recently to a phase 1 clinical trial. Based on the promising results in preclinical cancer models of ICG-001, an inhibitor of the β-catenin/CBP interaction (Le et al., 2015, Masuda et al., 2015), the second generation β-catenin/CBP antagonist PRI-724 was developed of which the clinical phase I trial in advanced solid tumors has been carried out (NCT01302405). Although the trial was terminated due to low patient enrollment, it revealed that PRI-724 has an acceptable toxicity (Lenz & Kahn, 2014) and as such, trials in subjects with acute and chronic myelogenous leukemia (AML/CML) are underway (NCT01606579). On the other hand, targeting of transcriptional regulation by YAP has proven to be difficult with verteporfin being the only compound able to inhibit the physical association between YAP and TEAD (Liu-Chittenden et al., 2012), although results obtained from a recently developed peptide that mimicks VGLL4, a TEAD interacting protein, are encouraging (Jiao et al., 2014). However, one of the most promising therapeutic strategies going forward, might be tankyrase inhibitors, such as XAV939, G007-LK, and JW55. These compounds have been proven effective in inhibiting both β-catenin-mediated and YAP/TEAD-mediated gene transcription in cancer (S. M. Huang et al., 2009, Wang et al., 2015), and have excellent pharmacokinetic characteristic in mice (Lau et al., 2013, Waaler et al., 2012).