Short summary

The project will investigate the activity/expression of the enzymes that play a part in glucose metabolism (GLUTs, hexokinases, glucose-6-phosphatase and HIF-1 alfa) and correlate this to the 2-deoxy-2-[¹⁸F]fluoro-D-glucose (FDG) uptake on PET/CT images in patients with non-small cell lung cancer(NSCLC)  and renal cell cancer.

Rationale

Positron emission tomography (PET) with the tracer 2-deoxy-2-[¹⁸F]fluoro-D-glucose (FDG) has been used since the late 1970's and there is still no unambiguous understanding of the correlation between glycolytic activity and FDG uptake in malignant cells even though it is well known that most malignant cells are hypermetabolic and have an increased glucose metabolism. False positives and false negatives occur, however, it is a matter of debate if and to what degree they represent true false findings or rather reflect true, but misinterpreted, conditions, due to the fact that most cancers comprise a continuum in aggressiveness and consequently also in the uptake rate of FDG.

Like glucose, FDG is transported into the cell via glucose transporters (GLUTs) and then phosphorylated by hexokinases (HK) to maintain the downhill gradient for transport of glucose into the cell. Due to subtle, but significant, chemical differences between FDG-6P and glucose-6P, FDG-6P is not a substrate for further metabolism in the glycolytic pathway. Gluts and hexokinases are upregulated in malignant cells of various types. The action of hexokinase can be reversed by glucose-6-phosphatase (G6Pase), and FDG can then leave the cell. However, tumor cells contain low levels of G6Pase, and FDG-6P is trapped inside the cell.   Hence, the FDG retention in malignant cells is thought to be mainly dictated by the concentration of G6Pase. Under hypoxic conditions, the levels of the transcription factor hypoxia-inducible factor 1alfa(HIF-1 alfa) increase leading to increased  gene expression of glycolytic enzymes such as GLUT1-5, HK-I-III and hence a higher FDG uptake in hypoxic cells. 

Kwee et al. illustrated this interplay in a review reporting increasing FDG uptake with increasing aggressiveness of the tumor type. This review states that "the key to the correct interpretation of oncological FDG-PET studies is awareness of the concept that the degree of FDG uptake reflects the biology of the tumor in many cancers. More specifically, cancers with high FDG uptake are often histologically and clinically more aggressive than those with low or no FDG uptake. Therefore, although a negative FDG-PET scan in a patient with a cancer that has a size above the spatial resolution of PET may be interpreted as false-negative in terms of tumor detectability, it should in fact be regarded as true-negative from the view-point of tumor biology".

Studies on various cancers have investigated the correlation between GLUT1-5, HK-I-III and G6Pase and the FDG uptake but have found ambiguous results and not all with significant findings. To our knowledge, there are no studies that have shown a significant correlation between G6Pase and FDG uptake, and there are no studies at all reporting the presence of all enzymes, except for a single one in head and neck cancer that looked at a few of the isoforms.

To further investigate the correlation between enzyme activity/expression and FDG uptake we will investigate different types of cancers known for having different degrees of FDG uptake, which has never been done before. NSCLC (adenocarcinoma and planocellular carcinoma) is known for having a high FDG uptake, whereas renal clear cell carcinomas are known for having a low FDG uptake.

Hence, the purpose of this study is to analyze the correlation between FDG uptake and the activi-ty/expression of GLUTs, hexokinases, glucose 6-phophatase and HIF-1 alfa in patients with either lung cancer with high FDG uptake or renal cell carcinoma with low FDG uptake. Furthermore, we wish to correlate the findings to the proliferation status of the tumors using a proliferation marker (Ki67) and, finally, correlate our findings to patient survival.

Description of the cohort

Twenty patients for each cancer type (adenocarcinoma and planocellular lung cancer and renal cell carcinoma) will randomly be selected from the Danish Cancer Biobank at OUH for inclusion.

Data and biological material

Clinical data including:

• Demographics (Age, sex, cancer type, time interval between PET/CT and surgery, TNM stage, performance status)
• Pathology description and immunohistochemistry stains and enzyme analysis for ki67, hexokinase, glucose transporters, glucose-6-phosphatase and HIF-1 alfa
• PET/CT scans standardized uptake values (SUV) including mean, total lesion glycolysis and peak value.

Collaborating researchers and departments

Department of Nuclear Medicine, Odense Universitetshospital

• Professor Poul Flemming Høilund-Carlsen, MD, DMSc
• Associate Professor Birgitte Brinkmann Olsen, MSc, PhD
• Associate Professor Oke Gerke, MSc, PhD
• Medical Student Eivind Antonsen Segtnan

Department of Pathology, Odense Universitetshospital

• Associate Professor Karen Ege Olsen, MD, DMSc

Publications associated with the project

Christlieb SB, Olsen BB, Segtnan EA, Gerke O, Olsen KE, Høilund-Carlsen PF. Biological mechanisms of FDG uptake in non-small cell lung cancer [abstr]. Eur J Nucl Med Mol Imaging 2016; 43(Suppl 1): 23: S478.