The p53 protein is mutated in over 50% of cancers. Because its expression often promotes tumor growth and is associated with resistance to treatment, there has been great interest in treating cancers based on p53 mutation status. However, the use of p53- targeted therapies requires knowing the mutation status. DNA sequencing is one approach, but requires invasive biopsies, and newer sequencing techniques still face technical hurdles. Non-invasive imaging techniques offer an alternative approach for detecting mutation status. Given that p53 regulates blood vessel growth, and that vessel imaging is used clinically to monitor response to cancer therapy, I hypothesize that tumor vessels could be used as an imaging marker to identify p53 mutation status. To test this hypothesis, I will measure relationships between p53 mutations and vessel structure/function using my expertise in 3D cell biology, vessel imaging, and image analysis and the unique expertise of the host lab in p53 biology, proteomics, and flow cytometry. The objectives of this interdisciplinary work are: 1) to screen the effect of p53 mutants on vessel structure in vitro; 2) to characterize the molecular response of endothelial cells to p53-targeted therapies; and 3) to image the structure and function of vessels in mutant p53 tumors in vivo. If a relationship is found between p53 mutation status and tumor vessel features, then it could lead to the development of the first imaging marker of p53 mutation status. This marker could help clinicians select p53-directed therapies to personalize therapy for each cancer patient. Apart from scientific impact, the proposed work will also expand my career prospects and scientific network in Europe. Under the mentorship of the host lab supervisor Prof. Sir David Lane, who discovered p53, I will receive focused training to strengthen and diversify the scientific and transferable skills I need to transition from postdoctoral scientist to junior group leader.
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