Therapeutic targets in neuroendocrine tumours.
Doctoral thesis, UCL (University College London).
BACKGROUND: Neuroendocrine tumours (NETs) are fairly rare neoplasms that present many clinical challenges. The complexity, heterogeneity, and rarity of NETs have contributed to their limited therapeutic options. To improve the outcome from NETs, a better understanding of their biology is needed. Several receptor targets exist, against whom agents such as antibodies or tyrosine kinase inhibitors are being developed and tested in clinical trials. Several of these agents have been used in combination with chemotherapy or radiation with promising results. These receptors include the tyrosine kinases EGFR and C-KIT, and the somatostatin receptor SSTR2. However, their role in neuroendocrine tumour growth remains unclear. METHODS: We investigated the anti-proliferative effect of EGFR inhibitor gefitinib, as single agent or in combination with widely used chemotherapeutic agents. The chemotherapeutic agents were also examined for their effect on EGFR activity. Cisplatin and radiation were studied for their effect in EGFR activity and localisation in combination with gefitinib and the anti-EGFR antibody cetuximab by immunoblotting and immunofluorescence, while the comet assay for quantitation of DNA damage was used to examine modulation of DNA repair by radiotherapy. The cytotoxic efficacy of agents against SSTR2 was also examined, while the expression of C-KIT was analysed in 95 NET patients by immunohistochemistry. RESULTS: Gefitinib demonstrated anti-proliferative effect associated with induction of apoptosis but no cell cycle arrest. Cisplatin induced a transient activation of EGFR and nuclear translocation, which was mediated through the Ras/MAPK and PI-3K/Akt signalling cascades. Cisplatin and radiation-induced EGFR translocation was blocked by gefitinib and cetuximab, and this was associated with a delay in the repair of radiation-induced DNA strand breaks. Nuclear translocation was mediated by nuclear pore complex importins and exportins, and utilized the EGFR nuclear localisation sequence. C-KIT was identified in a number of NET patients. The drugs against SSTR2 had no effect on the growth of cells. CONCLUSIONS: Targeting EGFR in combination with radiation may provide therapeutic potential in neuroendocrine tumours patients.
|Title:||Therapeutic targets in neuroendocrine tumours|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)|
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