Chemistry, mode of action and clinical efficacy of the anticancer diterpenoid tigilanol tigliate (EBC-46)

Tigilanol tiglate (EBC-46, 1), a novel diterpene ester isolated from the seeds of the endemic Australian rainforest tree Fontainea picrosperma (Euphorbiaceae), is being developed for intratumoral treatment of cancers in humans and companion animals [1],[2]. Here we summarise our current understanding of the chemistry and mechanism of action of the compound, and provide results from recently completed veterinary (Phase III) and human (Phase I/II) clinical trials.

Tigilanol tiglate has a multi-factorial mechanism of action. A single intratumoural injection (1) induces a rapid, highly localised and transient inflammatory response surrounding the tumour mass, (2) significantly increases permeability of the tumour vascular endothelium, and (3) causes rapid tumour cell death by oncosis. In combination, these result in tumour haemorrhagic necrosis, eschar formation and complete tumour destruction within 4 to 14 days. Localised inflammation and increasing permeability of tumour vasculature are associated directly with the activation by tigilanol tiglate of specific isoforms of protein kinase C (-βI, -βII, -α, -γ), while tumour cell death via oncosis requires PKC/C1 domain mediated signalling. The compound also induces changes in cytokine signalling and gene expression that promote wound healing following tumour destruction.

In a Phase III fully-randomised, controlled and blinded veterinary clinic trial, a single treatment with tigilanol tiglate resulted in complete and enduring tumour destruction in more than 75% of canine patients with mast cell tumours. In a clinical Phase I/II human dose-escalation study, maximum tolerated dose was not reached and signs of efficacy were observed in 9 tumour types, including complete response in 4 patients.

Fig. 1

• References

• 1 Barnett CME, Broit N, Ya PY, Cullen JK, Parsons PG, Panizza BJ. et al. Optimising intratumoral treatment of head and neck squamous cell carcinoma models with the diterpene ester Tigilanol tiglate. Invest New Drugs 2019; 37: 1-8.
• 2 Miller J, Campbell J, Blum A, Reddell P, Gordon V, Schmidt P. et al. Dose characterization of the investigational anticancer drug tigilanol tiglate (EBC-46) in the local treatment of canine mast cell tumors. Front Vet Sci 2019; 6: 106.