Therapeutic opportunities in mutant p53 cancer cells

This 4 year PhD studentship offered in Dr Patricia Muller’s research group is based at the Cancer Research UK Manchester Institute, Alderley Park, Cheshire

In our group we aim to understand the role of p53 and mutations in p53 in small cell lung cancer (SCLC). P53 is mutated in over half of all tumours and up to 90% in SCLC. Mutations can result in loss of p53, but can also give rise to mutant proteins that have lost some or all of p53 function. In addition, these mutant proteins often acquire novel function in driving invasion and metastasis and chemoresistance. Our lab is interested in how mutant p53 is acquiring these ‘gain-of-functions’. Remarkably, our recent work has revealed that under certain physiological circumstance even the wild type protein can act like a mutant protein by changing its conformation.

In this PhD project, we will investigate whether mutant p53 expression can be exploited as a therapeutic target directly or indirectly through synthetic lethality. Mutant p53 promotes cell engulfment of neighbouring cancer cells (Mackay et al 2018 Nature communications) by allowing engulfing cells to survive. In this project, we will determine the signaling molecules involved in the survival and explore if these can be targeted with existing drugs. We will investigate to what extent that influences tumour growth, chemoresistance and invasion/metastasis in vivo and in vitro. Mutant p53 is often overexpressed in cancers due to increased stability. Directly targeting mutant p53 specifically by influencing its degradation, stability and folding will therefore also be examined in this project.

The successful applicant should have or expected to gain a first or 2:1 bachelor’s degree in cell biology, oncology, biochemistry or a related field before October 2020. Experience in cell culture, cell signalling pathways and molecular biology is essential. Work experience with primary cell lines, animals, 3D cultures, microscopy or metabolism is not required, but will be advantageous.

Applications are invited from exceptionally high calibre students, graduates or final year undergraduates who should hold or are expected to gain a first/upper second-class honours degree in a relevant subject as part of a University degree course.

Applicants can find full group project details, entry criteria and details on how to apply online at:
http://www.cruk.manchester.ac.uk/education/PhD-Studentships

Closing date: Friday 3 January 2020 – 2100 hours GMT

Interview date: Tuesday 18 February 2020, Alderley Park, Cheshire