Tumor Markers for Targeted Imaging with Near-Infrared Fluorescence (NIRF) in Medullary Thyroid Carcinoma. A Genetic Tracking Approach.

Potze, A. (2015) Tumor Markers for Targeted Imaging with Near-Infrared Fluorescence (NIRF) in Medullary Thyroid Carcinoma. A Genetic Tracking Approach. thesis, Medicine.

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Abstract

Background: Medullary thyroid carcinoma (MTC) is a rare neuro-endocrine malignancy that arises from the calcitonin producing C-cells of the thyroid. Systemic therapies and radiotherapy turned out not to influence prognosis in MTC (1). Therefore, surgery is the only curative option. However, to obtain adequate tumor free marges during an operation is difficult, due to the difficulty in differentiating tumor from normal tissue (2,3). Besides, the extent of the dissection remains controversial as more radical surgery does imply more collateral damage to vital structures like nerves and does not necessarily translate into increased locoregional control nor disease-free survival (1,4,5). Therefore, ‘safety-first’ is often the predominant denominator during surgery prior to performing an extensive dissection at the time of the initial operation. A promising technique for obtaining adequate margins and to prevent the damage of healthy tissue is a novel platform technology for intraoperative image-guided surgery using near-infrared fluorescence (NIRF). This technique uses fluorescent agents that can attach to relevant biomarkers of cancer and light up the cancer cells (6). In order to design a thyroid cancer specific tracer for image-guided surgery, target identification is of the utmost importance to obtain the highest diagnostic accuracy in terms of sensitivity and specificity. Especially false positive rates are of a disadvantage for reaching the goals of more radical resection with a lower rate of collateral damage. Objectives: identify proteins and genes that are upregulated in MTC and can be used as a potential biomarker for optical imaging strategies. Material and methods: 1. Literature search for identifying proteins that are overexpressed in MTC, whereas the selected proteins are evaluated by the TArget Selection Criteria (TASC) for their suitability as a biomarker for optical imaging. 2. Identifying genes that are upregulated in MTC using functional genomic mRNA profiling (FGM profiling). The ten most upregulated genes are selected and the role of these genes (in cancer) will be evaluated using the literature. Results: the literature search identified 18 proteins that are upregulated in MTC. After applying TASC, 9 proteins were considered to be potential biomarkers which are; CAIX, CEA, HER2, MET, PDGFRβ, RET, VEGF-A and its receptors. The ten most upregulated genes from the non-biased FGM profile are; PHLDA2, CALCA, MICAL1, NBEA, CDC25B, CALCB, Bcl-2, TFF3, GCH1 and CACNA2D2. Of these genes overexpression was reported in five of these genes; CALCA, CDC25B, CALCB, Bcl-2 and TFF3. Discussion: FGM profiling is a new method for identifying genes that are upregulated in cancer and can lead to the identification of new potential targets for optical imaging purposes. To assess the suitability of these genes for tumor targeting, further research is necessary. Of the identified proteins, HER2 and VEGF-A are promising targets in MTC since they already showed good preclinical results of optical imaging using a clinically approved, fluorescent labeled agent (i.e. Bevacizumab and Trastuzamab) (7). Bevacizumab is currently in clinical trial for optical imaging Conclusion: This literature search and genetic tracking approach identified possible biomarkers that are overexpressed in MTC. To use these biomarkers for optical imaging purposes it is necessary to assess the expression of these biomarkers in MTC by means of histopathological analyses. Therefore, the next step is to perform immunohistochemistry using Tissue Micro Arrays (TMAs) on the selected biomarkers by our genetic screen.

Item Type:	Thesis (Thesis)
Supervisor name:	Faculty Supervisor: and Dam, Prof. dr. G.M. van and Department of Surgery, UMC Groningen
Faculty:	Medical Sciences
Date Deposited:	25 Jun 2020 10:44
Last Modified:	25 Jun 2020 10:44
URI:	https://umcg.studenttheses.ub.rug.nl/id/eprint/591

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