Identifying the determinants of tumour susceptibility to replication-inhibiting chemotherapy

Chromosome replication and maintenance are central for cell division, and derailment of these processes is a major cause of cancer. The protein RIF1 has emerged as a conserved regulator of chromosome maintenance, acting to control DNA replication and repair. Many of the most commonly used cancer chemotherapeutics act by blocking DNA replication and thereby inducing replication stress, and RIF1 is needed for cellular survival after treatment with chemotherapeutic drugs that induce replication stress. However how RIF1 ensures cellular recovery from replication stress remains mysterious, especially since of the two known splice variant isoforms of human RIF1, only one can mediate recovery from replication stress. The first part of this PhD project will investigate the mechanism through which RIF1 enables cellular recovery from replication stress, identifying and investigating the isoform-specific protein interactions that promote survival after replication-inhibiting drug treatment.

Interestingly, it has been suggested that the RIF1 isoform expression profile changes during carcinogenesis. Assessing RIF1 isoform expression could therefore potentially allow prediction of tumour response to this class of chemotherapeutics. Alongside testing the mechanism by which RIF1 protects cells from replication stress, in the second part of the project the student will test RIF1 isoform expression in patient-derived tumour samples. RIF1 isoform expression will be examined in tumour samples from single patients at different stages of treatment. Assessment of RIF1 expression and comparison with clinical history will establish whether RIF1 isoform expression provides a predictive biomarker for the effectiveness of replication-inhibiting chemotherapy. Tumour types for which such a biomarker would be clinically useful include gastro-intestinal, lung, and pancreatic cancers, all of which are treated with replication-inhibiting drugs. The availability of such a predictive biomarker assay would allow optimisation and personalisation of the therapy regime for patients, according to the molecular characteristics of their specific cancer. Such a biomarker test would save patients from ineffective treatment, and may inform development of new chemotherapeutics.

To summarise the two strands of the project: first, the student will investigate how which RIF1 mediates recovery from replication stress, identifying the mechanism through which only one of the two RIF1 isoforms promotes cell survival. Second, we will explore the changes in RIF1 isoform expression during carcinogenesis, and test RIF1 isoform expression as a predictive biomarker of tumour response to chemotherapeutic drugs that inhibit DNA replication.

Benefiting from an advisory team with highly complementary expertise as a basic molecular cell biologist and a clinical pathologist, this project exploits the location of the Institute of Medical Sciences at Aberdeen Royal Infirmary, and the resulting opportunities for productive collaboration and exploitation of fundamental understanding to improve cancer treatment.

APPLICATION PROCEDURE:
Formal applications can be completed online: https://www.abdn.ac.uk/pgap/login.php. You should apply for Degree of Doctor of Philosophy in Medical Sciences, to ensure that your application is passed to the correct person for processing.

NOTE CLEARLY THE NAME OF THE SUPERVISOR AND EXACT PROJECT TITLE ON THE APPLICATION FORM.

Further information on Cancer research at Aberdeen can be found here: https://www.abdn.ac.uk/smmsn/research/cancerabdn-1022.php