Inactivators of Ornithine Aminotransferase for the Treatment of Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the second or third leading cause of cancer mortality worldwide (depending on which statistics are used), yet there is no effective treatment. Currently, there are nine FDA-approved drugs for HCC, five monoclonal antibodies and four tyrosine kinase inhibitors. Ornithine aminotransferase (OAT) has been validated as a target in preclinical studies, which demonstrates that it is a potential target to treat HCC. Currently, there are no OAT inactivators in clinical trials for HCC. This Innovation describes evidence to support inhibition of OAT as a novel approach for HCC tumor growth inhibition. After the mechanism of OAT is discussed, the origins of our involvement in OAT inactivation, based on our previous work on mechanism-based inactivation of GABA-AT, are described. Once it was demonstrated that OAT inactivation does lead to HCC tumor growth inhibition, new selective OAT inactivators were designed and their inactivation mechanisms were elucidated. A summary of these mechanistic studies is presented. Inactivators of OAT provide the potential for treatment of HCC, targeting the Wnt/β-catenin pathway.

Differential OAT methylation correlates with cell infiltration in tumor microenvironment and overall survival postradiotherapy in oral squamous cell carcinoma patient

“…OAT methylation also correlated with numbers of pathways confirmed with tumor‐promoting effect 26 including focal adhesion, ECM receptor, MAPK, Wnt, and PI3K/AKT. Although it is only reported that upregulation of Wnt/β‐catenin pathway correlated with increased OAT expression promoted HCC progression and targeting OAT provided the potential for treatment of HCC, 15 this finding suggests a highlighted correlation of OAT methylation to cancer progression. Moreover, we investigated hypermethylated OAT was most prominently associated with increased sulfur metabolism.…”

“…7 In this study, we attempted to figure out the differential DNA methylation in OSCC compared to normal tissues and found only OAT (from top 20) methylation was significantly associated with the overall survival of OSCC patients. OAT is well known as a mitochondrial enzyme, which is essential for hepatocellular carcinoma (HCC) cells growth, 15 shedding light on the underlying interplay of OAT in cancer progression.…”

“…A few studies focusing on OAT expression in cancer progression provided some indirect evidences; it is shown in nonsmall cell lung cancer (NSCLC) that elevated OAT protein expression promoted cell proliferation, invasion and migration and inhibited cell apoptosis, 17 while inhibiting OAT expression blocked the tumor growth of HCC, implicating its potential to treat HCC. 15 Although there is no absolute cause-effect correlation between DNA methylation and gene expression, that methylation pattern was considered as more highly sensitive and capable to accurately predict tumor progression, 12 further providing indirect support for the association of OAT-related DNA methylation to cancer. The underlying association of OAT methylation with radiotherapy revealed that hypermethylated OAT was mostly occurred in radiationsensitive OSCC patients, indicating OAT methylation as a protector in response to radiotherapy.…”

Ornithine aminotransferase and carbamoyl phosphate synthetase 1 involved in ammonia metabolism serve as novel targets for early stages of gastric cancer

“…Previous studies suggested that OAT was a potential chemotherapy target for cancers. Silverman et al 14 have recently synthesized…”

“…Previous studies suggested that OAT was a potential chemotherapy target for cancers. Silverman et al 14 have recently synthesized OAT inactivators to inhibit the activity of OAT and lead to downregulation of l ‐Gln and growth inhibition of hepatocellular carcinoma through targeting the Wnt/β‐catenin pathway, which suggests that OAT was an important chemotherapy target for treatment of cancer. Zhu et al 15 recently showed that both human OAT and γ‐aminobutyric acid aminotransferase have a similar active site.…”