Pancreatic ductal adenocarcinoma (PDA) has a 5-year survival of only 11% and is projected to become the second leading cause of cancer-related deaths by 2030, therefore new treatment options are urgently needed. We have previously defined specific molecular subgroups of PDA associated with pre-clinical and clinical response to select tailored treatment strategies [1-2]. One such molecular-guided therapy, RXC004, a potent and selective inhibitor of the Wnt/β-Catenin pathway regulator porcupine, is being investigated in a phase II study in patients with pancreatic cancer (NCT04907851).
We have previously demonstrated interesting effects of tumour-cell targeted therapies on the environment of PDA [2-3], and here present pre-clinical data on the efficacy and anti-stromal effects of RXC004 in patient-derived genetically-defined and mouse PDA models. We determined the in vivo therapeutic efficacy of RXC004-based clinically relevant combinations with standard of care (SoC) chemotherapy in the context of tumour growth and overall survival. Mechanistic assessment of alterations in tumour cell-stromal cell cross-talk was performed using single cell RNA sequencing, spatial transcriptomics and immunofluorescence approaches.
In addition to reducing tumour growth in 2 pancreatic PDX models with confirmed loss-of-function mutations in RNF43, a negative regulator of the Wnt/β-Catenin pathway, RXC004 demonstrated striking anti-fibrotic effects in these settings, with changes in cancer-associated fibroblast populations, accompanied by decreased levels of extracellular matrix deposition, a hallmark of PDA. RXC004 monotherapy significantly improved survival in an aggressive orthotopic RNF43 mutant (G659fs) PDX model. Moreover, treatment with RXC004 as part of ‘priming’ and ‘maintenance’ regimens significantly improved in vivo chemosensitivity in the same setting. These data demonstrate that therapeutic efficacy of RXC004 and select anti-fibrotics in pre-clinical development may be the result of targeting both tumour cells and key aspects of the PDA microenvironment and in addition provide scientific rationale for the design of RXC004 plus SoC chemotherapy combinations in pancreatic cancer.