Greenwood, Hannah E.;
(2020)
Prediction of Drug Resistance in Preclinical Models of Cancer with System xc- Specific Positron Emission Tomography Radiotracers.
Doctoral thesis (Ph.D), UCL (University College London).
Abstract
Most cancer deaths result from the ineffective treatment of late-stage, metastatic disease. There is currently no adequate method to determine patients responding to treatment versus non-responders within a timeframe that permits intervention. Positron emission tomography (PET) imaging is a non-invasive tool that can be used to locate the underlying biochemical alterations that occur in patients with treatment-resistant disease, long before any anatomical changes are observed. Throughout this body of work, the transmembrane protein system xc- was examined as a target for imaging drug resistance in cancer using PET. System xc- is a plasma membrane antiporter that facilitates the exchange of intracellular glutamate for extracellular cystine. Once internalised, cystine is rapidly reduced to cysteine, a rate limiting amino acid in the biosynthesis of glutathione. Studies performed showed that the activity of this transporter, due to the intracellular concentrations of its amino acid substrates, was altered in cells which showed high levels of resistance to chemotherapeutics versus those which responded to treatment. With these findings, two fluorine-18 radiolabelled glutamate analogues were explored to measure system xc- activity, with tumour uptake values shown to predict response to treatment in preclinical models of lung and ovarian cancer. The ability to evaluate these radiotracers in vivo was facilitated through the development of a high throughput imaging bed used during preclinical PET imaging. This work has shown that a system xc- transported radiotracer may enable the identification of cancer patients resistant to standard-of-care therapy early following treatment, enabling their transferal to alternative therapy with the potential to prolong survival.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Prediction of Drug Resistance in Preclinical Models of Cancer with System xc- Specific Positron Emission Tomography Radiotracers |
| Event: | UCL (University College London) |
| Language: | English |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10111108 |
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