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Wnt-Signaling Pathway Inhibitor to Treat Advanced Tumours

Introduction
Figure 1: Diverse Wnt Signaling Pathways

Wnts are a family of 19 cysteine-rich morphogens that regulate a host of developmental and homeostatic processes. Wnt signaling pathways are highly conserved and play a critical role in a multitude of complex biological systems including embryonic development and tissue regeneration. The Wnt signaling pathways are often activated by the binding of the Wnt-protein ligand to a Frizzled receptor (see Figure 1).

Dysregulation of Wnt signaling promotes cancer growth and spread. Such dysregulation occurs in a subset of cancers with mutations in either upstream or downstream components of the signaling pathway. For instance, RNF43 and ZNFR3 loss-of-function mutations are found in cholangiocarcinoma, pancreatic and gastric cancers. These loss-of-function mutations increase Wnt signaling by making cancer cells more sensitive to Wnts.

Rationale

Wnt pathway driven cancers can be targeted at a number of steps in the pathway. Our approach is to target the secretion of all Wnts by inhibiting the enzymatic activity of Porcupine (PORCN). PORCN is an endoplasmic reticulum resident O-acyltransferase. PORCN catalyses the post-translational palmitoylation of Wnts at a highly conserved serine residue. This palmitoylation of Wnts is essential for their secretion and binding to Frizzled receptors. The inhibition of PORCN enzymatic activity also offers an approach to overcome the problem of redundancy of Wnts.

Current Status
Figure 2: ETC-159 is orally available
Figure 3: ETC-159 is effective therapy for HPAF-II RNF43 mutant, pancreatic cancer xenografts
Figure 4: Treatment with ETC-159 promotes differentiation (HPAF-II pancreatic cancer xenografts)
Figure 5: ETC-159 prevents growth of CR1 colorectal cancer PDX with RSPO3 translocations

The ETC is developing a potent orally available PORCN inhibitor, currently designated ETC-159. This small molecule drug candidate blocks the secretion and activity of all Wnts and is remarkably effective in multiple pre-clinical cancer models including several RNF43-mutant pancreatic cancers and RSPO-translocation bearing colorectal cancers. The inhibition of Wnt signalling by ETC-159 causes a marked remodelling of the transcriptome, with loss of cell cycle, stem cell and proliferation genes and an increase in differentiation markers i.e. it suppresses cancer proliferation and prevents cancer progression.

ETC-159 entered Phase 1 clinical trials in June 2015, with the trials being conducted at the National Cancer Centre Singapore and the National University Hospital. The trials will be extended to the US at a later date. The clinical trials will evaluate the safety and tolerability of ETC-159 in advanced solid tumours.

Summary
  • Drug candidate: ETC-159
  • Type: small molecule drug
  • Target: Wnt signaling pathway
  • Therapeutic Area: oncology
  • Indications: colorectal, ovarian and pancreatic cancers
  • Stage of development: Phase 1
 
  1. Madan B, Virshup DM. Targeting Wnts at the Source-New Mechanisms, New Biomarkers, New Drugs. Mol. Cancer Ther. 2015;14(5):1087–1094.
  2. Madan B, Ke Z, Harmston N, et al. Wnt addiction of genetically defined cancers reversed by PORCN inhibition. Oncogene. 2015.
  3. Duraiswamy AJ, Lee MA, Madan B, et al. Discovery and Optimization of a Porcupine Inhibitor. J Med Chem. 2015;150716085031000