Shah, T.H.; (2010) The study of epidermal growth factor receptor, 99mTechnetium-depreotide, and tumour markers in the management of neuroendocrine tumours. Doctoral thesis , UCL (University College London).

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Abstract

Purpose: Neuroendocrine Tumours (NETs) are rare and therefore poorly understood. Their slow progression and general poor response to standard chemotherapy regimes implies that their tumour biology is significantly different from most common cancers. There have been major advances in the past few decades in the diagnosis and management of these tumours which are perceived to be associated with improvements in quality and length of life. However, since most NETs have metastasised extensively by the time of diagnosis it is a major challenge indeed to try and effect tumour regression – the ultimate goal of any anti-cancer therapy. Chapters: 2 & 3: The epidermal growth factor receptor (EGFR) is commonly expressed in human tumours and provides an important target for therapy. Several classes of agents including small molecule inhibitors and antibodies are currently under clinical evaluation. These agents have shown interaction with chemotherapeutic agents in vitro and in vivo. However, the mechanisms of these interactions are not clearly understood, particularly in regards to NETs. The purpose of this study was to investigate the expression of EGFR in NET tissue and to determine its mechanisms of action, as well as the effects of modulation of EGFR activation. Experimental Design (Chapter 2): Paraffin-embedded tumour tissue was available from 98 patients with NETs (39 foregut, 42 midgut, four hindgut, five paragangliomas, and four of unknown origin). Immunohistochemical evaluation was performed for the expression of EGFR, p-EGFR, p-Akt, and p-ERK1/2. Results: Ninety-six percent of tumour samples were positive for EGFR expression; 63% were positive for activated EGFR; 76% were positive for activated Akt; and 96% were positive for activated ERK1/2. Importantly, the histological score for the activation of Akt and ERK1/2 correlated with the histological score for activated EGFR. These data provide a rationale for considering EGFR inhibitors in the treatment of NETs. Additionally, direct inhibition of Akt and ERK1/2 may provide further therapeutic options in the treatment of NETs in the future. Experimental Design (Chapter 3): The effects of the EGFR inhibitors gefitinib and erbitux were determined in several NET cell lines. The modulation of DNA-PK activity by these agents was quantitated using a variety of techniques including immunoprecipitations, immunoblotting, cellular fraction extractions and immunohistochemistry. Results: Prolonged EGFR inhibition leads to reduction in DNAPKcs concentration in all tested NET cell lines except RIN, which displays the lowest levels of EGFR expression. This reduction in DNAPKcs is likely to lead to sensitisation of NET cells to ionising radiation, which causes double-strand DNA breaks, DNAPKcs being crucial to their repair. There are direct EGFR/DNAPKcs interactions in NET cell lines, which can be enhanced by EGFR inhibition. EGFR inhibition leads to transfer of DNAPKcs from the nucleus to the cytoplasm in SHP and BON cell lines but not in CRI, RIN, or NCI cell lines. This difference in the observed outcomes may be due to the lack of or mutations in intermediary proteins, though proof is needed for this hypothesis. The re-distribution of DNAPKcs is likely to lead to sensitisation of NET cells to ionising radiation, which causes double-strand DNA breaks, DNAPKcs being crucial to their repair. Chapter 4: Surgery is at present the only therapy with the possibility of achieving a cure. Therefore optimising diagnostic modalities in order to discover the tumours early or to discover all the tumour lesions prior to surgery would be of use. The purpose of this project was to assess the role of 99mTc-depreotide in patients with negative or weakly positive OctreoScan® (Krenning score \geq 1; measured on a scale range 0-4). To determine the usefulness of 99mTc-depreotide scintigraphy for highlighting lesions that may be missed by OctreoScan® and/or CT/MRI imaging. Experimental Design: Prospective analysis of 25 NET patients, with negative or weakly positive ¹¹¹In-pentetreotide scans, who were consecutively enrolled to undergo ¹¹¹In-pentetreotide and 99mTc-depreotide imaging. The results were compared with either CT or MRI scans. Results: Histology was available for 20 of 25 patients: of these 40% had high grade tumours (cellular proliferation marker Ki67 score > 20%), a further 35% had intermediate grade tumours (Ki67 2-20%), and the remainder 25% had low grade tumours (Ki67<2%). 52% of patients had completely negative and 48% had weakly positive OctreoScan®. 32% of these same patients had significantly positive 99mTc depreotide scans (Krenning score \geq 2), with the histology demonstrating intermediate or high grade tumours. Chapter 5: Some NETs follow an indolent course compared to others which display a rapidly progressive course with only short-lived response to therapy. Being able to confidently predict the long-term prognosis is obviously desirable. The aims of this project were to determine the diagnostic and prognostic value of serum alphafetoprotein (AFP) and human chorionic gonadotrophin beta (hCG\beta) in NETs. Patients and methods: a database containing biochemical, histological, and survival data on 360 NET patients was constructed. This data was statistically assessed, using SPSS statistics package, to determine the utility of commonly measured tumour markers with particular emphasis on AFP and hCG\beta. Results: AFP and hCG\beta were raised in 9.5% and 12.3% of patients respectively, and jointly raised in 9.1% of patients in whom it was measured. AFP levels associated strongly and positively with tumour grade, serum CgA, hCG\beta levels and worse survival. hCG\beta levels also associated strongly and positively with serum CgA, AFP levels and worsening survival.

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