The efficacy and mechanism of action of EBC-46 in head and neck squamous cell carcinoma

Adams, Ryan Andrew (2013). The efficacy and mechanism of action of EBC-46 in head and neck squamous cell carcinoma MPhil Thesis, School of Medicine, The University of Queensland.

       
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Author Adams, Ryan Andrew
Thesis Title The efficacy and mechanism of action of EBC-46 in head and neck squamous cell carcinoma
Formatted title
The Efficacy and Mechanism of Action of EBC-46 in Head and Neck Squamous Cell Carcinoma
School, Centre or Institute School of Medicine
Institution The University of Queensland
Publication date 2013-01
Thesis type MPhil Thesis
Supervisor Benedict Panizza
Glen Boyle
Peter Parsons
Benjamin Wallwork
Total pages 101
Total colour pages 31
Total black and white pages 70
Language eng
Subjects 110315 Otorhinolaryngology
111207 Molecular Targets
111204 Cancer Therapy (excl. Chemotherapy and Radiation Therapy)
Formatted abstract
Head and neck squamous cell carcinoma (HNSCC) is the fifth most common cancer world-wide with an unchanged 50 percent five-year survival rate over the past 30 years. Novel approaches to this disease burden has shifted toward molecular targeted therapies aimed at inducing cancer cell senescence and host immune system activation to promote regression and clearance of malignant cells. EBC-46 is a newly identified diterpene ester and known Protein Kinase C (PKC) activator developed by QBiotics Pty. Ltd. which has shown immense promise in many solid tumours in veterinary practise leading to complete tumour clearance with a minimal side effect profile and a low incidence of recurrence.

The aim of this body of work was to explore the efficacy of EBC-46 in two human HNSCC cell lines in a mouse model whilst also probing into the understanding of its mechanism of action both in-vitro and in-vivo. In-vitro studies focused on HNSCC cell survival in treated media to investigate its efficacy in culture. With western blot analysis the expression of PKC in HNSCC and its subsequent activation by EBC-46 was confirmed. Through the subcutaneous inoculation of malignant cells into nude mice, HNSCC xenografts of both CAL 27 (tongue) and FaDu (hypopharyngeal) SCC subtypes were able to be established and consequently treated with a single intra-tumoural injection of 30 μg of EBC-46 and contrasted to the injection of its vehicle (10 mM Sodium Acetate in 20% Propylene Glycol pH4.5) alone as a control.

This study has shown that EBC-46 has the potential to ablate human HNSCC in a murine model within 21 days without evidence of recurrence up to 90 days following treatment in 65 percent of cases. In-vitro investigations, however revealed that the cytotoxic capacity of the compound does not match that seen in-vivo, achieving a mean cell reduction of 30.2 percent across both cell lines. This data suggest that EBC-46 is more efficacious in-vivo than in-vitro, indicating a co-dependent mechanism of action involving both primary necrosis and a significant host response culminating in tumour clearance. The confirmation of PKC activation by EBC-46 was provided by western blot analysis in culture and the downstream effects on the tumour microenvironment were followed by cytokine flow cytometry and histopathology verifying the stimulation of an innate immune response. This research confirms that the intra-tumoral delivery of EBC-46 into human HNSCC xenografts kills tumour cells leading to tumour ablation, a result achieved through the activation of PKC isoforms and the stimulation of a local immune response.
Keyword Head and neck squamous cell carcinoma
Protein Kinase C
Phorbol Ester

 
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Created: Sat, 24 Aug 2013, 09:03:23 EST by Ryan Adams on behalf of Scholarly Communication and Digitisation Service