Singapore Scientists Reveal a Metabolic Pathway as a New Target in Liver Cancer Treatment
Study showed that two metabolic enzymes in the proline metabolic pathway are potential targets to inhibit cancer cell growth, and offers new hope for effective liver cancer treatments
SINGAPORE, 7 January 2020 – Researchers at A*STAR’s Singapore Bioimaging Consortium (SBIC) have identified two new possible drug targets for liver cancer treatment. They found that a metabolic pathway for the production of an amino acid called proline, controlled by key genes named PYCR1 and ALDH18A1, was essential for cell proliferation and tumour growth in hepatocellular carcinoma (HCC), the predominant form of liver cancer. This means that finding ways to inhibit the activity of PYCR1 or ALDH18A1 may pave the way towards therapeutic strategies targeting HCC. The research study also provided insights into metabolic changes specific to liver cancer development. The study was a collaboration between A*STAR’s SBIC and Institute of Medical Biology (IMB), the National Cancer Center Singapore (NCCS), and the Pharmaceuticals Division of Bayer1]; its findings were published in the Journal of Hepatology in November 2019.
Cancer is a very complex disease. The ability of cancer cells to rewire their metabolism to promote cell growth and proliferation, also known as metabolic reprogramming, plays a pivotal role in their ability to survive and replicate. HCC is the sixth most common cancer worldwide and considered to be the second deadliest cancer for men and sixth for women[2]. Studies have shown that clinical benefits of available liver cancer treatments are limited[3].
The research team led by Prof. Han Weiping, Deputy Director of SBIC and Head of the Laboratory of Metabolic Medicine, aimed to identify targets for developing effective treatments for HCC, by characterising the metabolic shifts in this disease. Tapping on SBIC’s multi-disciplinary capabilities in metabolomics, metabolic imaging, and cancer metabolism, the researchers compared the metabolic enzyme expression profiles of different laboratory models with those from liver tissues of normal and regenerating liver models.
The team demonstrated that the proline biosynthesis pathway, was essential for maintaining a metabolic state that supports the unrestrained growth of HCC tumours. The PYCR1 and ALDH18A1 enzymes involved in proline biosynthesis were found to be highly expressed in HCC tumours, while the depletion of these enzymes suppressed cancer cell proliferation. It was also notable that the team’s analysis of The Cancer Genome Atlas (TCGA) cohort revealed that patients who had low expression levels of PYCR1 or ALDH18A1 had significantly better survival rates. The data from the cohort also indicated that these associations remained significant even after adjusting for different patient and tumour characteristics such as age, tumour stage, tumour grade, radiation therapy, prescription therapy and additional therapies.
These findings collectively suggest that the proline biosynthesis pathway may be a specific and effective target in the treatment of HCC, and the key genes in the pathway PYCR1 and ALDH18A1 may offer a novel therapeutic strategy for liver cancer. Moving forward, the team plans to conduct small molecule screening for drug target validation of PYCR1 and ALDH18A1.
Prof. Han said, “Findings from this study highlight the importance of advancing our understanding of cancer metabolism to identify the main drivers of cancer. By identifying novel factors that can be targeted, our study paves the way for new treatments that can help patients who fail to fully respond to currently-available drugs. As we pursue PYCR1 and ALDH18A1 as targets in liver cancer treatment, we will also test whether these enzymes are also valuable targets for other cancers.”
Prof. Toh Han Chong, Deputy Medical Director (Strategic Partnerships) of NCCS and a co-author of the study said, “These findings create
Link to online version of the scientific paper: (https://linkinghub.elsevier.
[1] Scientists and researchers who contributed to the studies include Weiping Han, Zhaobing Ding, Russell Ericksen, Qian Yi Lee from SBIC, Nathalie Escande-Beilllard, Abigail Loh, Simon Denil and Bruno Reversade from IMB, Timothy Wai Ho, Pierce Chow and Han Chong Toh from NCCS, and Sylvia Gruenewald, Michael Steckel and Andrea Haegebarth of the Pharmaceuticals Division of Bayer.
[2] Source: Journal of Clinical and Translational Hepatology 2018, vol. 6
[3] Source: Journal of Clinical and Translational Hepatology 2018, vol. 6