Inhibiting the Epidermal Growth Factor Receptor (EGFR) to improve clinical outcomes for patients with Squamous Cell Carcinoma of the Head and Neck (SCCHN)

Abstract

Advanced squamous cell carcinoma of the head and neck (SCCHN) is a debilitating disease with an unmet need for effective treatment options. The epidermal growth factor receptor (EGFR) is a logical therapeutic target due to its high prevalence of overexpression, pivotal role in carcinogenesis and prognostic significance. However, current EGFR-targeted therapies have shown only modest clinical success due to their dose-limiting toxicities (DLTs) associated with the concurrent inhibition of wild-type (WT) EGFR signalling in normal tissues (e.g. skin rashes and diarrhoea). Tarloxotinib bromide (also known as SN33999, PR-610, TH-4000 and RN-4000) is a prodrug designed to release an irreversible pan-ErbB inhibitor (known as TH-4000E) selectively within the hypoxic regions of tumours. This prodrug approach may allow for tumour dose intensification by circumventing the normal tissue toxicities associated with conventional EGFR-targeted therapies and superior clinical outcomes for patients with advanced SCCHN. Mechanistic studies show that TH-4000E is more dose potent than current clinical-stage EGFR-targeted therapies for advanced SCCHN and is deactivated by 13- to 67-fold relative to TH-4000 under normoxic conditions. The O2-dependence of TH-4000 metabolism was measured and complete inhibition was observed above 0.1 μM O2 and through the physiological range indicating a requirement for severe hypoxia that is unique to solid tumours. An in silico spatially-resolved pharmacokinetic/pharmacodynamic (SR-PK/PD) modelling approach was used to show the potential for tumour dose intensification. The approach is based on an earlier O2 transport model developed in a representative mapped tumour microvascular network using the Green's function methods. The mathematical framework for this model was modified to include in vitro determined reaction and diffusion reactions for TH-4000 and TH-4000E to simulate their steady state distribution with respect to O2 in a digitised three-dimensional (3D) tumour microregion. After a standard clinical dose of TH-4000, TH-4000E concentrations were consistent with in vitro cytotoxicity at 98% of the tissue voxels in the simulated tumour microregion. Model simulations were supported by the superior silencing of WT EGFR signalling and anti-tumour activity with TH-4000 compared to standardof- care cetuximab in a human tumour xenograft model of advanced SCCHN. Prospective TH-4000 combinations for advanced SCCHN were explored using a series of antiproliferative, clonogenic, spheroid growth delay and tumour growth delay assays. Preliminary studies show that the anti-tumour efficacy of TH-4000 is potentiated by standard treatment modalities (radiation, cisplatin and cetuximab), however further investigation is required to determine the optimal approach. Overall, this thesis demonstrates that TH-4000 is a hypoxia-activated prodrug (HAP) of a dose potent EGFR inhibitor with optimal properties for tumour dose intensification and therapeutic potential for patients with advanced SCCHN.