Novel Therapeutic Agents for the Treatment of Head and Neck Squamous Cell Carcinoma: Preclinical Feasibility and Veterinary Clinical Application.
Abstract: Head and
neck squamous cell carcinoma (HNSCC) is a debilitating disease, with more than 630,000
new cases diagnosed worldwide each year. Greater than 60% of these patients are
diagnosed at a locally advanced disease-stage where prognosis remains poor despite
aggressive multi-modal treatments involving radical surgery, radiation and chemotherapy.
Novel therapeutic agents are therefore ... read morewarranted that will have efficacy in this
vulnerable patient population. My dissertation work has focused on characterizing
engineered, tumor-targeted versions of anthrax lethal toxin with potential therapeutic
utility in HNSCC. Previously, three separate versions of anthrax protective antigen
(PrAg) had been designed, which required activation by the tumor-overexpressed
proteases, matrix metalloproteinases (MMPs) and/or urokinase plasminogen activator
(uPA). When these engineered PrAg variants were co-administered with various cytotoxins,
they were selectively activated within the tumor microenvironment and they exhibited
potent anti-tumor activity in multiple preclinical models of cancer. However,
simultaneously with reports of dramatic anti-tumor efficacy, toxicities of varying
severity had been reported with their use. To address toxicity concerns and evaluate the
feasibility of further developing these engineered anthrax lethal toxins, I performed
in-depth toxicological and efficacy profiling. I identified that an engineered variant
requiring co-localized activation by both MMPs and uPA, IC-PrAg + LF, was an optimal
lead candidate. IC-PrAg + LF exhibited a clear therapeutic window for use in C57BL6/J
mice and was highly effective at treating B16-BL6 melanoma syngrafts; at a dose 6 fold
below its no observed adverse effect level (NOAEL) a 58% reduction in tumor burden was
achieved. IC-PrAg + LF was then further evaluated for preclinical anti-HNSCC activity
using four separate xenografted human HNSCC cell lines. In all cases dramatic reduction
in tumor volume was observed. The greatest antitumor response was seen in HN12
xenografts, where 40% of treated mice (6 of 15) had complete tumor regression. Building
upon this finding, IC-PrAg + LF has now been translated to a clinical setting. A Phase 0
veterinary clinical trial has been initiated in cats with spontaneously occurring oral
cancer. While this trial is still in progress, initial findings are highly encouraging.
The first patient had a measurable, 31%, reduction in tumor volume following receipt of
three intratumoral microdose treatments. Collectively, this dissertation research
demonstrates that an engineered variant of anthrax lethal toxin requiring co-localized
activation by MMPs and uPA, IC-PrAg + LF, is a promising candidate for further
development as an anti-HNSCC agent for both human and veterinary patient
Thesis (Ph.D.)--Tufts University, 2014.
Submitted to the Dept. of Pharmacology & Experimental Therapeutics.
Advisors: Thomas Bugge, and David Greenblatt.
Committee: Philip Hinds, Martin Beinborn, and Alexei Degterev.
Keywords: Pharmacology, Toxicology, and Veterinary science.read less