A study using preclinical models has discovered a drug combination with the potential to treat one of the most fatal and globally widespread cancers, a type of primary liver cancer called hepatocellular carcinoma (HCC).
The collaborative research team found the drug combination reverses the symptoms of nonalcoholic steatohepatitis (NASH) and, subsequently, markedly reduces the onset of NASH-driven HCC, without affecting the liver when tested using preclinical models.
The study, published in Science Advances, used a model that mimics human NASH-driven HCC to implement a combination treatment of an endoplasmic reticulum (ER) stress inhibitor called ‘BGP-15’ with the inflammation blocker, ‘Olamkicept’.
Both of these drugs are already proven to be safe in humans and have progressed to Phase 2 and 3 human clinical trials for other metabolic and/or inflammatory diseases.
Professor Alistair Forrest, Head of the Perkins Systems Biology and Genomics Laboratory, said liver cancer poses a significant threat to global health and this discovery could offer hope for those facing this insidious disease.
“Hepatocellular carcinoma is now the fifth most common cancer worldwide, with a worrying 18% five-year survival rate,” Professor Forrest said.
“HCC is increasing at an alarming rate partly due to issues such as obesity and type 2 diabetes, which may lead to NASH, a well known HCC risk factor,” said Professor Forrest.
The rise in HCC coincides with patients presenting with obesity and symptoms associated with the metabolic syndrome, especially metabolic dysfunction-associated fatty liver disease (MAFLD). Globally, a staggering 25 per cent of the population are estimated to be living with MAFLD, with around 15 per cent of those exhibiting signs of NASH.
Study lead author Professor Mark Febbraio from Monash University, said despite the high prevalence of NASH and the alarming rise in NASH-driven HCC, there are currently no FDA approved treatments that halt disease progression.
“Given that ER stress and inflammation are hallmarks of NASH-driven HCC, and that BGP-15 and Olamkicept have both already proven to be safe, we tested whether these drugs – as monotherapy, or in combination – would prevent NASH and/or NASH driven HCC in preclinical models.
“Consistent with our hypothesis, the study shows that while monotherapy with either of the two drugs modestly slowed progression, when combined they have shown to be a realistic therapeutic strategy for treating human NASH and progression to HCC, diseases that are rapidly growing with a clinical unmet need.”
Professor Febbraio said that given the significance of the discovery, combined with the urgent need for new safe and effective treatments for NASH and NASH-driven HCC, the team ultimately hope their findings will progress toward clinical trials.
“We have to stress that this study was not performed in humans. However, as both drugs have been shown to be safe in several human clinical trials, the logical next step is testing the BGP-15/Olamkicept combination in clinical trials for patients with NASH and or HCC.”
The study was conducted in collaboration with The Garvan Institute of Medical Research; The Salk Institute of Biological Studies based in California; the Faculty of Veterinary Science, University of Sydney; the Baker Heart and Diabetes Institute; the Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia; Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University; Department of Biochemistry, Christian-Albrechts-Universität zu Kiel, based in Germany and the Department of Pharmacology, University of California San Diego, La Jolla, based in California.
Originally published at Scimex: https://www.scimex.org/?a=934731
Read the full publication here: https://www.science.org/doi/full/10.1126/sciadv.adh0831?af=R