517MO Phase I study of the porcupine (PORCN) inhibitor RXC004 in patients with advanced solid tumours

Targeting ligand-dependent wnt pathway dysregulation in gastrointestinal cancers through porcupine inhibition

“…No grade 4/5 adverse events or bone fragility events were reported, with patients receiving prophylactic denosumab. Five patients, all with Wnt pathway activated tumors, had stable disease, including one patient with biliary tract cancer, and two CRC patients with either an RNF43 mutation or a RSPO fusion ( Cook et al, 2021 ).…”

“…The latter likely arises because Wnt signaling has been shown to be vital for proliferation of taste-progenitors and formation of taste buds ( Gaillard et al, 2017 ; Prochazkova et al, 2017 ). Prophylactic treatment with bisphosphonates or denosumab has been shown to mitigate increases in bone turnover markers ( Cook et al, 2021 ; Tan et al, 2018 ). Encouragingly, gastrointestinal side effects appear to be limited and manageable.…”

The emerging era of personalized medicine in advanced colorectal cancer

“…58 Several porcupine inhibitors have entered Phase I clinical trials and have been shown to decrease β-catenin and Wnt3 levels, downregulating Wnt signaling and stimulating cancer cell dormancy. 59,60 They have shown promise in the treatment of different types of cancer, including CRC, hepatocellular cancer and pancreatic cancer. 58 A recombinant fusion protein, Ipafricept, which acts as a FZD decoy receptor, competes with FZD receptors by binding directly to Wnt ligands.…”

719 Phase 1 study of the porcupine (PORCN) inhibitor RXC004 in combination with the PD-1 inhibitor nivolumab in patients with advanced solid tumors

“…Ruth Plummer. 1 University of Manchester, The Christi, Manchester, UK; 2 Oxford University Hospitals, Oxford, UK; 3 Royal Marsden Hospital, London, UK; 4 Guy's Hospital NHS Trust, London, UK; 5 The Freeman Hospital, Newcastle-upon-Tyne, UK; 6 University of Manchester, The Christie, Manchester, UK; 7 RedX Pharma Plc, Alderley Edge, UK; 8 RedX Pharma, Alderley Edge, UK Background Tumour-derived Wnt-ligand signalling leads to a reprogramming of the immune microenvironment and is implicated in intrinsic and adaptive resistance to Immune Checkpoint Inhibitor (ICI) therapy. Specifically, Wnt-ligand signaling is correlated with reduced CD8+ve T-cell infiltration, 1 and ICI resistance 2 in multiple cancers.…”

“…This abstract reports the second module of a multi-modular adaptive design protocol (NCT03447470). The first module was previously reported 6 and the recommended Phase 2 dose (RP2D) for RXC004 monotherapy was 2mg QD. Methods This was an open label, 3+3 dose escalation study.…”