Therapy resistance is one of the biggest problems currently facing clinical oncology, with most cancer deaths resulting from ineffective treatment of drug-resistant cancer. Through this project, we will develop an innovative preclinical programme of research to non-invasively image and treat drug resistant breast cancer through the creation of novel theranostic agents (Fig. 1). Theranostics describes the use of radioactive drugs or biomolecules for both treatment (thera-) and diagnosis (-nostics) of cancer. The tumour-targeting agent, in this case a small molecule, will be tagged with a radionuclide. By switching the radioisotope from a positron to an alpha/beta emitter we can use the same agent for imaging or treatment, respectively.
We will use these theranostics to target the very pathways that cause drug resistance. Drug-resistant tumours upregulate numerous antioxidant pathways that both counteract drug-induced oxidative stress and increase drug efflux. We will target aldehyde dehydrogenase 1A1, a cancer stem cell marker, which is upregulated many-fold in drug-resistant breast cancer. During your PhD you will develop an extensive range of experimental skills spanning in vitro mechanistic evaluation of drug-resistant cancer (flow cytometry, western blotting, biochemical assays, CRISPR/Cas9), to in vivo assessment in advanced animal models of breast cancer (orthotopic, PDX, isogenic). Our objectives over the course of your PhD will be to:
• Yr1: Select appropriate cell model, evaluate specificity, perform cell binding of theranostics, understand biochemical mechanism of cell-kill, perform genetic knockdown and over-expression of target
• Yr2: Perform imaging of lead theranostic to determine compound distribution, tumour binding and dosimetry
• Yr3: Undertake treatment studies in vivo, optimise dosing schedule, determine therapeutic index, publish results
• Yr4: Expand work to other cancer types, publish findings
