Abstract
Head and neck cancers account for 3% of all newly diagnosed cancers, of which 90% are
squamous cell carcinomas (SCC). Improvements in surgery, radiotherapy and chemotherapy
have done little to improve the mortality of this disease over the past 20 years while current
clinicopathological predictors of disease outcome are sub-optimal. Identifying molecular targets
of prognostic and therapeutic significance in head and neck squamous cell carcinomas
(HNSCC) may help direct novel therapies to patients whom it is most likely to benefit. Accrued
knowledge of the biology of HNSCC has highlighted specific aberrations in pRb and p53
pathways which warrant further study.
An immunohistochemical analysis (IHC) in a cohort of 145 patients with SCC of the anterior
tongue was performed. Protein expression of the pRb and p53 pathways and related molecules
that directly or indirectly influence cell cycle progression at the G1/S phase checkpoint was
assessed. We determined that over-expression of E2F-1 occurred in >35% of these cancers
and associated with improved overall survival on univariate analysis. The strongest multivariate
model included: regional lymph node status, tumour grade, p16INK4A, cyclin D1 and p14ARF. This
is the first study to determine that p14ARF is an independent marker of both improved diseasefree
survival and overall survival in a cohort of SCC of the anterior tongue.
Unrecognized molecular heterogeneity is thought to account for the unpredictable clinical
response to ZD1839, an EGFR tyrosine kinase inhibitor. We explored the anti-proliferative
effects following ZD1839 treatment alone or in combination with radiotherapy in cyclin D1 and
E2F-1 over-expressing SCC9 HNSCC cells. SCC9 cells over-expressing cyclin D1 or E2F-1
were highly resistant to ZD1839 treatment, while E2F-1 clones were also radioresistant.
Combined therapy in SCC9 controls had a greater anti-proliferative effect than each individual
treatment. These data showed that cyclin D1 and E2F-1 may have utility as markers of ZD1839
resistance.
The data in this thesis contribute to our knowledge of the clinical behaviour and molecular
pathology of HNSCC. Specifically the molecular data identifies novel markers of outcome in
SCC of the anterior tongue such as p14ARF, and therapeutic response to ZD1839 such as cyclin
D1 and E2F-1. This study addresses in part, the current issues and limitations of management
in HNSCC and has the potential to contribute to strategies that may be developed to improve
the outcome for patients who develop HNSCC in the future.