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Despite improvements in treatment, the prognosis for patients with advanced head and neck squamous cell carcinomas (HNSCC) has only improved to a minor degree. To raise the success rate and minimize morbidity further developments in diagnostics are highly desired. Radioimmunodiagnosis could offer a more specific and sensitive diagnostic method. Herein, we have evaluated different radioimmunoconjugates directed against CD44v6 and epidermal growth factor receptor (EGFR) for imaging of HNSCC. The studies were performed in a murine HNSCC xenograft model. Initially, the 111In-labeled anti CD44v6 chimeric monoclonal antibody U36 (cMAb U36) was evaluated. The novel radioimmunoconjugate showed high and accumulating tumor uptake. Since small molecules might be advantageous for imaging, due mainly to their shorter circulation half-life in the bloodstream, we then investigated antibody fragments F(ab’)2 and Fab’ derived from cMAb U36. The highest tumor-to-blood ratio was achieved with the dimeric antibody fragment F(ab’)2, compared with both the intact anti-body and monomeric Fab’. Furthermore, the possibility of improving EGFR-targeted imaging was explored by pre-blocking EGFR. The liver uptake of injected labeled human epidermal growth factor (hEGF) was significantly reduced when an excess of unlabeled hEGF was injected 30 minutes in advance. However, as hEGF stimulates cell proliferation it may be inadvisable to treat cancer patients with large amounts. Alternatively, pre-blocking with an anti-EGFR Affibody molecule (ZEGFR:955)2 demonstrated similar decrease in liver uptake as unlabeled hEGF. Finally, (ZEGFR:955)2 was compared with other Affibody molecules with higher affinity to EGFR, ZEGFR:1907 and (ZEGFR:1907)2, as pre-blocking agents. In addition, a novel hEGF radioimmunoconjugate, [67Ga]Ga-NOTA-Bn-NCS-hEGF was used for EGFR targeting. The dimeric (ZEGFR:1907)2 showed greatest reduction in non-tumor uptake, and highest tumor-to-organ ratio in EGFR expressing organs, when injected in advance of the radioimmunoconjugate. To summarize, the results presented here demonstrate how different radioimmunoconjugates as well as pre-blocking EGFR can improve the radioimmunodiagnosis of head and neck squamous cell carcinomas.

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).

Thesis (Ph.D.)--Edith Cowan University, 2006. / Submitted to the Faculty of Computing, Health and Science. Includes bibliographical references.

Diss. (sammanfattning) Umeå : Univ., 2004. / Härtill 6 uppsatser.

Diss. (sammanfattning) Umeå : Univ., 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Göteborg : Göteborgs universitet , 2007. / Härtill 5 uppsatser.

Dissertation (Ph.D.).--University of Texas Graduate School of Biomedical Sciences at San Antonio, 2007. / Vita. Includes bibliographical references.