ETC-159, an Upstream Wnt inhibitor, Induces Tumour Necrosis via Modulation of Angiogenesis in Osteosarcoma.

There is an increasing urgency in the search for new drugs to target high-grade cancers such as osteosarcomas (OS), as these have limited therapeutic options and poor prognostic outlook. Even though key molecular events leading to tumorigenesis are not well understood, it is widely agreed that OS tumours are Wnt-driven. ETC-159, a PORCN inhibitor that inhibits the extracellular secretion of Wnt, has recently progressed on to clinical trials. In vitro and in vivo murine and chick chorioallantoic membrane xenograft models were established to examine the effect of ETC-159 on OS. Consistent with our hypothesis, we noted that ETC-159 treatment not only resulted in markedly decreased ß-catenin staining in xenografts, but also increased tumour necrosis and a significant reduction in vascularity-a hereby yet undescribed phenotype following ETC-159 treatment. Through further understanding the mechanism of this new window of vulnerability, therapies can be developed to potentiate and maximize the effectiveness of ETC-159, further increasing its clinical utility for the treatment of OS.

Porcupine inhibitors: Novel and emerging anti-cancer therapeutics targeting the Wnt signaling pathway.

Porcupine is a constituent of the 19 membered Wnt family with diverse biological features such as cell differentiation, cell proliferation, cell migration, apoptosis, etc. Porcupine is a membrane-bound o-acyltransferase family protein that modulates Wnt protein through palmitoylation to allow it to depart the secretory pathway and activate cellular responses. Inhibition of Porcupine prevents palmitoylation of Wnt ligands which in turn blocks the transport of Wnt to the extracellular membrane, thus prevents the immoderate production of ß-catenin which helps to control the aberrant cell growth. Clinically, Porcupine inhibitors have shown their potential in treating majorly colorectal cancer, pancreatic cancer, hepatocellular carcinoma, head and neck cancer etc. Till date, none of the Porcupine inhibitors have been in the market and only four molecules, LGK974, ETC159, CGX1321 and RXC004 have reached the Phase I clinical trial. Present review gives a comprehensive insight on Porcupine as a novel drug target for the treatment of cancer as well as recent update on many novel heterocyclic Porcupine inhibitors with their chemical structures and pharmacology. Their physico chemical properties were also predicted using SwissADME server. Major concerns during their development have also been summarised which may throw some light for the future development of novel Porcupine inhibitors for the treatment of cancer.