Novel Drug Targets & Cell Line for Hepatocellular Carcinoma

James Cook University have developed unique transplantable cell lines from a syngeneic model of murine HCC on the C57B/6 background. The cell lines can be used for in vitro and in vivo drug screens. As an example, we used in vitro & in vivo studies to illustrate the efficacy of a combinatorial therapy of 2 drugs: rapamycin and dasatinib (Figure 1).

Figure 1. Combination therapy of 2 drugs studied using our novel lines for HCC showing synergistic effect in in vivo studies.

Researchers have also identified 3 novel drug targets for HCC from animal model studies. Western blot confirmed the expression of the corresponding proteins in HCC cell lines & primary NASH HCCs. The genes have functions in metabolism, cell division & double strand DNA repair. We used siRNA to study effects of gene knockdown of the lead target, involved in dsDNA repair, on the activity of cisplatin (Figure 2).

Figure 2. Reduced gene expression of target gene 9 (TSV1) increased lethality of cisplatin.

• The cell lines & animal models show good similar pathology between parental & transplanted tumour.
• The drug targets are novel & can be used to develop first-in-class therapies.

• The cell lines can be used for screening drug candidates.
• The drug targets can be used for developing novel drugs and combination therapies against HCC & other cancers.

James Cook University are seeking partners for early-stage research support & co-development.

2019 goals:

• Further target validation in vitro & in vivo
• Relationship to DNA repair
• Validation with known drugs e.g. sorafenib, lenvatinib, regorafenib
• Assay development

The studies will lead to a dug discovery & development program using the novel target.

2020-22 goals:

• Optimise assays & being high-throughput screens (HTS)
• Complete HTS using compound libraries
• Conduct biochemical & cell-based tests of promising lead.

The JCU research team has extensive experience in research in metabolism, gene expression, siRNA/shRNA use, mouse models and cell biology.

Research infrastructure includes cell culture, mouse house, metabolic analysers, cell biology equipment, equipment for protein and RNA evaluation.

Seeking:

• Development partner
• Commercial partner
• Licensing

• A/Prof Lionel Hebbard