Basic Research

Basic Research

The following projects represent some of the research that will expand the molecular and functional imaging programs at the Edmonton PET Centre.

Development of novel PET probes for molecular imaging.

Alzheimer’s disease

In a project led by Dr. Jack Jhamandas (Tier 1 Canada Research Chair, Alzheimer’s disease), we have commenced a new program (2003) to design novel PET tracers for understanding, diagnosing and treating Alzheimer’s disease. In spite of recent advances in new radiopharmaceuticals for the clinical evaluation of Alzheimer’s disease (AD), positron emission tomography (PET) is not currently in routine use. The significant roles of amyloid cascades and neurofibrillary tangles in the pathogenesis of AD have led us and other researchers to develop a biomarker that facilitates early diagnosis of the disease and that is specific for these markers of disease so that it serves as a true diagnostic tool for anti-amyloid therapies. A recent study suggests that anti-amyloid therapies, when co-investigated in combination with amyloid imaging tracers, could facilitate in vivo evaluation of the efficacy of therapy in the aging human brain.

For more information please see the following powerpoint poster.

Imaging Islet Cell Transplants

Our group has investigated a specific probe for the Glutathione (GLUT)-2 transporter. Our hypothesis is that this transporter will be specific to pancreatic islet cells. Human islet cell transplantation has been developed by the Transplant Research Group at the University of Alberta (Dr. Shapiro). We have cloned the GLUT-2 transporter (Dr. Cheeseman) and have confirmed the hypothesis of specificity for the GLUT-2 transporter with a tritiated probe. Based on this pilot study data we have completed a funding request to CIHR to expand the study with the synthesis of a fluorinated analog of the tritiated probe to be used in in vitro studies, and as the F-18 product in PET imaging studies. A series of experiments will be performed to confirm our hypothesis that imaging with a GLUT-2 transporter probe can detect and quantify islet cell mass, viable fraction and viable mass at multiple time points post transplant. These parallel experiments will be performed in an islet transplant animal models with an animal scanner, and in humans using the PET/CT scanner. It is our further hypothesis that a specific GLUT-2 transporter can be used to quantify remaining functioning islet cell mass in patients with diabetes. Integrated functional and anatomical imaging with the PET scanner will be key to answering the questions posed to us by the islet cell group in defining functional mass and the distribution of islets within the hepatic parenchyma post transplant. We also propose to examine the role of GLUT-2 transporter imaging in a population of patients with breast cancer where in vitro data suggest GLUT-2 is the dominant transporter.

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Radiopharmaceutical development for predicting treatment response, evaluating treatment response, and monitoring patient outcomes.

Develop in vivo markers that will predict the failure of chemotherapy agents.

There are now compelling data in the literature showing that some cases of treatment failure are correlated with patients who rapidly metabolize chemotherapy agents with the presence of multi-drug resistance gene and with patients who have altered renal or hepatic handling of chemotherapy agents. These metabolic differences between patients are in some patients genetically controlled. Our hypothesis is that, by labeling the chemotherapy agents of interest with PET tracers and correlating their in vivo findings with, for example polymorphisms identified by Dr. Sawyer and integrated with the Polyomx database, we will be able to develop in vivo markers for identifying patients who have altered handling of these chemotherapy agents. Further we hypothesize that the ability to perform integrated functional anatomical imaging in these patients will enable us to better identify those patients who have mixed populations of tumors where different metastases not only functionally vary from the original primary but also functionally differentiate among themselves. We believe that these mixed populations are likely to have mixed response. By identifying prospectively these patterns of likely mixed response, we will be able to modify treatment plans to account of these functional differences.

Evaluation of changes in metabolic activity following therapeutic intervention.

A new, innovative and expanding area for improving treatment decisions in patients with cancer is to correlate patient outcome with gene or Single Nucleotide Polymorphism (SNP) profiling of tumor samples obtained by biopsy or at surgery. The Alberta Cancer Board has established a large tumor bank with integrated clinical and profile databases to prospectively monitor patients referred for treatment. The project includes patients from most tumor groups. Our hypothesis is that the correlation of in vivo quantitative metabolic markers, using PET probes such as 18F-fluorodeoxyglucose (FDG) and the nucleoside analog 18F-fluorothymidine (FLT), with the gene and SNP profiles and the clinical outcomes database will enhance our understanding of treatment effects and the prediction of treatment response. The PET imaging will be used at the time of biopsy or surgery, using the interventional component of the PET/CT scanner to ensure that the biopsy is performed at the site of maximum metabolic activity within the tumor. These parameters will also be measured during the course of treatment to evaluate changes in metabolic activity with therapeutic intervention.

Known clinical PET agents worked up and provided for research initiatives.

This includes fluoroestradiol used to map estrogen receptor expression in breast cancer patients, 11C choline used in an upcoming prostate cancer study and 18F fluoride used to monitor the therapeutic potential of anticancer therapy in a mouse model of metastatic bone disease.

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Technology development to provide access to additional radionuclides.

Our long term objectives include the development of a reliable 124I high-yield target and automated recovery system, with eventual integration into radioiodination automated synthesis units. Although production schemes exist for this radionuclide, we will develop and refine existing targetry systems to take advantage of the high current capabilities of the cyclotron. Once the 124I system has been developed we will adapt the high-current target system to produce other radionuclides such as 64Cu and 86Y.

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Radiotherapy treatment planning.

The Centre for Biological Imaging and Adaptive Radiotherapy (CBIAR) at the Cross Cancer Institute arose from two successful CFI proposals (PET and Tomotherapy). These projects led to the development of a state-of-the-art facility that provided a unique array of tools to enhance radiotherapy delivery through integrated functional and anatomical imaging within the treatment plan. The treatment can be modified during the course of therapy to increase dose to remaining areas of functioning tumor; either demonstrated by FDG (glucose metabolism) or FLT (DNA synthesis) or by utilizing a 18F labelled nitroimidazole nucleoside analogue (FAZA) to demonstrate residual functioning hypoxic tumor. The conversion of our PET scanner to a PET/CT unit will increase our ability to demonstrate residual functional tumor volume within an anatomic mass prior to and during courses of IMRT or tomotherapy. The hypothesis that control and possibly cure can be achieved by using this technique will be tested initially in patients with non-small cell lung cancer, small cell lung cancer and head and neck cancers, and ultimately expanded to other tumor groups. Secondary objectives are to develop a better image fusion algorithm and to utilize functional imaging to measure and quantify normal tissue damage and the degree to which it can be avoided using IMRT and tomotherapy.

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Evaluation of the biological effects of radioisotope therapy.

The Nuclear Medicine group at the Cross Cancer Institute runs an extensive radioisotope therapy (RIT) program with conventional I-131 mIBG, In-111 Octreotide, I-131 iodide and Sr-89 strontium treatments as well as trials of investigational radiopharmaceuticals labeled with I-131 and Y-90. An in vitro laboratory has been established in collaboration with Dr. David Murray to investigate the radiobiology of very low dose-rate irradiation, with a view to developing an understanding of the molecular basis for the radiation response seen with RIT. We have recently initiated an investigation using antisense oligonucleotides as probes to evaluate expression of P-21, following irradiation that will enhance our understanding of the way in which this form of radiation therapy delivery can be utilized in the clinic and also understanding the mechanisms of enhancing clinical efficacy. Antisense oligonucleotides (as-ODNs) are small synthetic nucleotide sequences that can bind to their complementary ‘target’ mRNA. Various methods for synthesising radiolabeled as-ODNs as PET imaging probes are under development. PET has the potential to measure cellular responses to chemotherapy/XRT without the need for invasive techniques such as biopsies. Given the key role of p21Waf1/Cip1 gene activation in the cellular response to IR both in vitro and in vivo, the ability to non-invasively monitor changes in the levels of this transcript in situ would potentially provide a major tool for evaluating tumour and normal tissue responses to XRT during treatment. Such information would ultimately allow the clinician to make treatment decisions and design interventions on the basis of dynamic molecular responses to therapy. Developing this approach in Alberta will also set the table for the design, synthesis and implementation of other as-ODN PET probes for any mRNA species of interest that might provide insight into the processes of carcinogenesis and treatment response.

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An exploration of the molecular mechanisms that FLT utilizes to cross plasma membranes

C. Cass and R. Paproski

18F-3′-fluoro-3′-deoxythymidine (FLT) is a relatively new PET imaging agent which preferentially accumulates in proliferating tissues. Currently, there are few studies which have elucidated the molecular mechanisms utilized by FLT to cross plasma membranes. To determine the role of the nucleoside transporter mENT1 in FLT uptake, 6 wildtype mice, 6 heterozygous mENT1+/- mice, and 6 mENT1 knock-out mice will undergo dynamic imaging (60 minutes) with the MicroPET using [18F]FLT in order to observe any differences in FLT uptake between mice strains. Six additional wildtype mice will undergo [18F]FLT microPET imaging twice, with or without prior injection of phosphorylated NBMPR, an ENT1 inhibitor, to see if biodistribution of [18F]FLT in mENT1 knock-out mice can be reproduced in wild-type mice with the ENT1 inhibitor. To better determine the distribution of [18F]FLT in mice strains, mouse tissues will be excised and monitored for radioactivity using a gamma counter 60 minutes after [18F]FLT injection. Excised spleen tissues will be taken from mice in order to verify mENT1 and thymidine kinase 1 protein levels as well as ATP levels. The goal of the project is to determine the role of ENT1 on the pharmacokinetics of FLT.

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