Optimising intratumoral treatment of head and neck squamous cell carcinoma models with the diterpene ester Tigilanol tiglate

Abstract

SummaryThe five-year survival rate for patients with head and neck squamous cell carcinoma (HNSCC) has remained at~50% for the past 30 years despite advances in treatment. Tigilanol tiglate (TT, also known as EBC-46) is a novel diterpene ester that induces cell death in HNSCC in vitro and in mouse models, and has recently completed Phase I human clinical trials. The aim of this study was to optimise efficacy of TT treatment by altering different administration parameters. The tongue SCC cell line (SCC-15) was identified as the line with the lowest efficacy to treatment. Subcutaneous xenografts of SCC-15 cells were grown in BALB/c Foxn1 nu and NOD/SCID mice and treated with intratumoral injection of 30 μg TT or a vehicle only control (40% propylene glycol (PG)). Greater efficacy of TT treatment was found in the BALB/c Foxn1 nu mice compared to NOD/SCID mice.Immunohistochemical analysis indicated a potential role of the host's innate immune system in this difference, specifically neutrophil infiltration. Neither fractionated doses of TT nor the use of a different excipiant led to significantly increased efficacy. This study confirmed that TT in 40% PG given intratumorally as a single bolus dose was the most efficacious treatment for a tongue SCC mouse model.

Use of the Intratumoural Anticancer Drug Tigilanol Tiglate in Two Horses

“…Following treatment with tigilanol tiglate, the tumors in both equine patients followed a pattern of clinical response consistent with that seen and reported with the drug in other species and tumor types including canine mast cell tumors ( 1 , 3 ), a variety of human neoplasias ( 4 ), and murine tumors ( 2 , 5 ). This clinical response is directly related to the mode of action of tigilanol tiglate in tumor destruction and involves localized bruising and inflammation/oedema developing at the treatment site within the first 24 h, followed by haemorrhagic necrosis of the tumor mass and finally slough of the necrotic tumor leaving a treatment site wound which usually heals uneventfully via secondary intention without the need for bandaging or other interventions ( 1 ).…”

“…Tigilanol tiglate (also known as EBC-46) is a novel small molecule approved in the European Union and United Kingdom as an intratumourally-administered, veterinary pharmaceutical for treatment of non-metastatic, non-resectable canine mast cell tumors ( 1 ). It is also under clinical evaluation as an intratumoural treatment for a range of other cutaneous and subcutaneous cancers in humans and companion animals ( 2 – 4 ). Tigilanol tiglate is a potent cellular signaling molecule with a multifactorial mode of action that induces (a) a rapid, acute and highly localized inflammatory response in and immediately surrounding the tumor mass, (b) recruitment of immune cells, (c) loss of tumor vasculature integrity and (d) induction of tumor cell death by oncosis ( 5 ).…”

Phase I dose-escalation study to determine the safety, tolerability, preliminary efficacy and pharmacokinetics of an intratumoral injection of tigilanol tiglate (EBC-46)

“…Tigilanol tiglate (EBC-46) is a novel short-chain diterpene ester derived from the seeds of the native Australian blushwood tree ( Fontainea picrosperma ) [6] and is currently in development for the local treatment of a broad range of tumors [[7], [8], [9]].…”

“…Tigilanol tiglate induces a respiratory burst from human polymorphonuclear leukocytes [7] and when injected directly into a tumor, increases vascular endothelial permeability, provokes mitochondrial swelling and plasma membrane destruction in tumor cells, inhibits the growth and induces cell death of a number of human tumor cell lines [9]. It also induces a transcriptional profile with the characteristics of a Th1 immune response, suggesting an immunomodulatory effect that may play a role in tumor regression [10].…”

“…Preclinical studies employing murine xenograft models showed that a single IT injection of tigilanol tiglate produced vascular disruption, hemorrhagic necrosis, an acute highly localized inflammatory response, rapid tumor cell death and regression of solid tumors [7,9,10,18]. In addition, numerous veterinary clinical studies have demonstrated that tigilanol tiglate administered IT was effective against neoplasms such as cutaneous mast cell tumors and soft tissue sarcomas [8,18,19].…”