published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Surgery / Master / Master of Research in Medicine

published_or_final_version / Medicine / Master / Doctor of Medicine

No description available.

Receptor Tyrosine Kinase (RTK) inhibitors, such as erlotinib/tarceva, have been introduced in the past decade as a promising therapeutic option in Head and Neck Squamous Cell Carcinoma (HNSCC), however, they lack significant efficacy as single agents. As a result, RTK inhibitors require a combination based therapeutic approach with other treatment modalities. To uncover such a combination of agents, we performed a high throughput Prestwick library screen that included 1200 compounds approved by the FDA on HNSCC cell lines and found that monensin, a coccidial antibiotic, synergistically enhanced the cytotoxicity of erlotinib. RT-PCR revealed that monensin induced the expression of Activation of Transcription Factor (ATF) 3 and its downstream target C/EBP homologous protein (CHOP) which are key regulators of apoptosis. Furthermore, RNA-Seq analysis suggests that monensin augments erlotinib cytotoxicity by disturbing lipid and sterol biosynthesis. Therefore, identifying the mechanism of action exerted by monensin may open alternative avenues of cancer treatment.

No description available.

Context: Squamous cell carcinoma (SCC) is the second most common skin cancer. Ultraviolet radiation (UVR) exposure, its most important risk factor, has mostly been investigated in cross-sectional study designs. This study presents a comprehensive and longitudinal examination of determinants of SCC, including photoageing. Objective: To examine the determinants of SCC and its precursor condition of photoageing. Above all, the objective was to investigate the interplay of phenotypic traits; occupation and leisure-time sun exposure patterns; and personal exposures, in particular, tobacco smoking and life course sun exposure, upon the risk of SCC and photoageing. Setting and Design: This investigation formed part of a large community-based, long-term cohort study of skin cancer. The Nambour Skin Cancer Study (forthwith, the Nambour Study) began in 1986 and concluded in 2007. In 1986 a random sample of 2095 people (aged 20-69 years) from Nambour, Queensland participated in a skin cancer survey. In 1992, a 5 year field trial to assess the preventive actions of sunscreen and beta-carotene was initiated (n=1621). Regular full skin examinations were conducted to determine the presence of skin cancer and actinic skin damage. In 1994, participants detailed their life course sun exposure (n=1290). After the trial ended in 1996, participants continued to complete regular questionnaires and ascertainment of skin cancers continued to 2007. Participants: The participants were 1339 unselected adults aged 25 to 75 years who had taken part in the Nambour Study in 1992 and consented to the follow-up study. Methods: Life course sun exposure hours were estimated from questionnaires and the approximate UVR exposure for Nambour (latitude 26S) was determined. Descriptive analyses examined patterns of exposure within the population. Factors influencing the severity of photoageing were also investigated. Informed by these analyses, relative risks were calculated for determinants of SCC and population attributable risk percentage (PAR%) for key modifiable risk factors. To investigate tobacco smoking as a risk factor for SCC, systematic review and meta-analysis were performed. Exposure measures: Pigmentary phenotype, estimated UVR exposure, tobacco smoking, sun-related behaviours, e.g. sunscreen use. Outcome measures: Incident and histologically proven SCC of the skin from 1992 to 2007 was the main outcome assessed. Photoageing, assessed clinically and micro-topographically (Beagley and Gibson scale), was an intermediate outcome measure and an objective measure of cumulative sun exposure in the final SCC analysis. Results: Examination of self-reported UVR revealed mean annual exposures were highest in early life and older adulthood (older than 60 years.) Women reported spending less time in the sun than men in all stages of life (p<0.05) and the more sun-sensitive the person’s skin type, the less sun exposure was reported at each life stage. The role of tobacco smoking in cutaneous SCC was reviewed in the published literature and a small positive association was noted in the meta-analysis. However, few studies had adjusted, or adjusted adequately, for sun exposure. Within the Nambour Study, with adjustment for age, sex, skin phenotype, lifetime sun exposure, current and former smoking had no association with SCC (RR 1.2, 95%CI 0.7, 2.0 and RR 1.1, 95%CI 0.8, 1.5, respectively compared with lifelong non-smokers). In this study population, with moderate to severe photoageing at study baseline, increasing age, male sex, a sun-sensitive phenotype were found to increase the odds of more severe actinic damage (p<0.05). High or very high UVR exposure in adulthood predicted a greater severity (OR 2.2, 95%CI 1.3, 4.0). Finally, the determinants of SCC were examined. Increasing age (4% increase per year of life, 95%CI 3% to 5%), male sex (RR 1.4, 95%CI 1.1, 1.9) and fair skin (RR 4.7 95%CI 2.0, 11.4) were associated with SCC. Having light eye colour and fair or red hair also significantly increased SCC risk. Recalled life course sun exposure overall was not found to be associated with SCC. Signs of actinic damage at baseline were, however, very strongly associated with SCC. Recent sun exposure, defined as that reported in the period (1-2 years) before the occurrence of SCC or for those unaffected at the end of the study, was also examined. A strong positive association was found between high recent exposure and SCC (RR 2.1, 95%CI 1.3, 3.3). PAR% estimates of prominent modifiable risk factors for SCC suggested considerable potential for reduction in incidence for at-risk populations if recent sun exposure were reduced. Conclusions: Subjective measures of solar UVR exposure and objective measures of photoageing varied according to personal and phenotypic factors. The interplay between risk factors observed here highlight the need to control for confounding in investigating solar factors as causes of skin cancer. Although SCC occurred on the background of high cumulative UVR exposure, which was best determined with objective rather than recalled measures, recent UVR exposure was also important. Self-reported recent exposure being less subject to recall bias than reported life course exposure may have partly influenced this, but the impact of UVR acting as a tumour initiator and promoter is also likely to explain the relation of SCC to sun exposure in the recent past.

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 &gt35% 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.

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 &gt35% 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.

Thesis (Ph. D.)--Ohio State University, 2007. / Title from first page of PDF file. Includes bibliographical references (p. 109-124).