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Targeting treatment resistence in Liver cancer

Our team’s research into liver cancer has recently been published..

A paper entitled, ‘Dual Targeting of Sorafenib-Resistant HCC-Derived Cancer Stem Cells’ has recently been published in the published in Current Oncology with Dr Aparna Jayachandran and team. This work has been conducted in close collaboration with liver cancer researchers at the Gallipoli Medical Research Institute and the University of Queensland, Brisbane.

Hepatocellular carcinoma (HCC) is a cancer that begins in the liver. Liver is a football-sized organ located in the right side of the abdomen. It is essential for digesting food and ridding body of toxic substances. Unfortunately, HCC is typically diagnosed late in its course, with a median survival of approximately 6 to 20 months. The 2 years survival is less than 50% and 5-year survival is only 10%.

Sorafenib, a multi-tyrosine kinase inhibitor, is the first-line therapy for advanced HCC. However, not all patients respond to Sorafenib treatment due to the development of Sorafenib resistance. Circumventing resistance to Sorafenib by targeting the molecular mechanisms contributing to Sorafenib resistance is imperative.

The group investigated a rare and aggressive tumour subpopulation called cancer stem cells (CSC). They found that the interplay of CSC with immune checkpoints and epithelial-to-mesenchymal transition leads to Sorafenib resistance. We have found that a therapeutic approach targeting the CSCs can be an effective treatment modality for HCC.

Currently there are limited treatment modalities for advanced HCC patients. Our findings provide a valuable strategy to potentially improve the clinical efficacy of Sorafenib in patients with advanced HCC.

Congratualtions to the research team on this paper.

Dr Aparna Jayachandran has also published research with fellow FECRI scientist Dr Prashanth Prithviraj on liver cancer entitled Combined inhibition of TGF-β1-induced EMT and PD-L1 silencing re-sensitizes hepatocellular carcinoma to Sorafenib treatment’ in the Journal of Clinical Medicine. Dr Prithviraj is the second author and Dr Jayachandran is the senior and corresponding author on this publication. This work has been conducted in close collaboration with liver cancer researchers at the Gallipoli Medical Research Institute and the University of Queensland, Brisbane.

This work also focused on Hepatocellular carcinoma (HCC) increased therapy resistance and circumventing resistance to oral multi-tyrosine kinase inhibitor, Sorafenib. Circumventing resistance to Sorafenib by exploring and targeting possible molecular mechanisms and pathways contributing to Sorafenib resistance is an area of pressing need.

The current study focuses on epithelial-to-mesenchymal transition (EMT), a cellular process which confers HCC tumour cells with the ability to evade the immune system and develop resistance to Sorafenib treatment. The present study is the first to examine the association between cytokine transforming growth factor (TGF)-β1-induced EMT, aberrant immune checkpoint expression and Sorafenib resistance in HCC. Notably, this is the first study to report that combined inhibition of TGF-β1-induced EMT and immune checkpoint PD-L1, can re-sensitize HCC cells to Sorafenib treatment. We conclude that the combination of TGF-β receptor kinase inhibitor and immune checkpoint inhibitor can synergistically impeded EMT and potentially improve the sensitivity of HCC cells to Sorafenib. These findings provide a valuable strategy to potentially improve the clinical efficacy of Sorafenib in HCC patients by utilizing combinatorial treatment approach with PD-L1 blocker and TGF-β inhibitor.