iOnctura, a clinical-stage biotech developing selective cancer therapies against targets that play critical roles in multiple tumour survival pathways, has published new research data in the peer-reviewed journal Cancer Research, that supports a strategy of combining autotaxin inhibitor IOA-289 with TGF-β pathway inhibitor IOA-359.
Resistance to TGF‐β pathway inhibition
The research, generated in collaboration with the lab of Professor Davide Melisi, Associate Professor of Medical Oncology at the Department of Medicine, University of Verona, uncovers a central role for autotaxin in resistance to TGF‐β pathway inhibition.
The TGF-β pathway plays a critical role in promoting tumour aggressiveness, immune escape and resistance to therapy, which has made it an attractive target for cancer therapy. Previous attempts to interrupt TGF-β pathway signaling in cancer have been thwarted by activation of alternative resistance pathways by the tumour. By characterising these resistance mechanisms, iOnctura is designing novel, safe combination treatments that promise to override resistance.
Professor Davide Melisi said: “We have uncovered a new mechanism of action for autotaxin in resistance to TGF‐β pathway inhibition. Data generated by our laboratory across in vitro and in vivo models and from human clinical samples support this important finding. These findings pave the way for clinical studies combining autotaxin inhibitors with TGF-β pathway inhibitors, addressing the fibrotic barrier that protects tumours and reversing immunosuppressive mechanisms encouraging the immune system to mount an attack against cancer cells.”
Catherine Pickering, Chief Executive Officer of iOnctura, said: “These data support the clinical development of autotaxin inhibitors in combination with TGF-β inhibitors and standard of care for the treatment of pancreatic cancer. This validates our strategy of combining IOA-289, iOnctura’s clinical stage autotaxin inhibitor, with IOA-359, our TGF‐β inhibitor that we are preparing for clinical development.”
Research outcomes and observations
The published research showed that blocking the TGF‐β pathway in vivo or in in vitro co-culture models increased the number of autotaxin-producing inflammatory cancer associated fibroblasts (iCAFs). The autotaxin enzyme in turn increased lysophosphatidic acid (LPA) NF- κB signaling in tumour cells which triggered treatment resistance.
Specifically, NF-kB promoted CXCL1 expression and recruitment of myeloid suppressive cells (MDSCs), that limited CD8 T-cell infiltration. Adding the autotaxin inhibitor IOA-289 to TGF-β pathway inhibitor galunisertib and standard of care in PDAC-bearing mice, suppressed NF-κB signaling, reduced MDSC and increased CD8 T-cell infiltration, resulting in prolonged overall survival and curing 40% of the mice.
Most importantly, pancreatic ductal adenocarcinoma (PDAC) patients treated with galunisertib from the H9H-MC-JBAJ trial, had significantly elevated levels of autotaxin compared to patients in the control arm. Median progression free survival was shorter for those with higher autotaxin levels compared to those with lower.