Investigation of the mechanism of accrued resistance to Pol I inhibitors in blood cancers

OVERVIEW

An elevated level of ribosomal RNA (rRNA) production supports the uncontrolled growth of cancer cells and as a result they become “addicted” to abnormal level of rRNA. Consequently, cancer cells become more sensitive to drugs that target rRNA production, making rRNA production a promising target for anticancer therapy. The first drug that targets rRNA production (CX-5461) has recently entered the clinical trials against advanced blood cancers and more such drugs are currently under development. Our recent research demonstrated that although CX-5461 very efficiently kills blood cancer cells, the cells can become resistant to the drug, meaning the tumours recur. We believe we have identified a cause for CX-5461 resistance by discovering that a protein named topoisomerase-II-alpha, which is often overproduced in aggressive cancers, mediates activity of CX-5461 in blood cancer cells. Understanding of how blood cancer cells develop resistance to drugs targeting rRNA production will allow us to develop better drugs in the future. These drugs will represent a viable and less damaging alternative to chemo- and radiotherapy which are widely used to treat blood cancers. Confirming Topoisomerase-II-alpha’s role in the development of the resistance will allow us to identify and select patients who will benefit most from CX-5461 treatment. In collaboration with Australian National University, Canberra.

CX-5461 is the first selective Pol-I transcription inhibitor (PTI) that entered clinical trials against haematological malignancies. We showed that CX-5461 very effectively treats syngeneic models of blood cancers that are resistant to standard therapies and have a dismal prognosis. Although the increase in survival afforded by CX-5461 was spectacular, mice eventually relapsed and developed tumours insensitive to CX-5461. Our preliminary data suggest the link between acquired resistance to CX-5461 and the level of Topoisomerase-IIα expression/activity in cells. However, the nature of this link and mechanism of the resistance are not known and defining the molecular events that regulate Topoisomerase-IIα-dependent resistance to PTI is the main objective of this project. To achieve this we will test our hypothesis suggesting a special role for low-intensity double-strand DNA breaks localised at the ribosomal DNA in the drug’s efficiency and investigate changes in transcriptome of drug-resistant cells. We will use cellular models as described in details in our research plan aiming eventually to translate our findings to the clinic.

The outcomes of the proposed research will have impact in the area of therapeutic potential of PTI for treatment of haematological malignancies especially those that are resistant to other treatments, thus benefiting blood cancer sufferers.

All applicants must meet the academic entry requirements: https://www.qub.ac.uk/courses/postgraduate-research/biological-sciences-phd.html#entry

Research Information

PhD Supervisors
Information on the research interests and activities of academics in Biological Sciences can be accessed via the School website and the Find a Supervisor facility.

Career Prospects

Introduction
Queen’s postgraduates reap exceptional benefits. Unique initiatives, such as the DegreePlus/Future Ready Award, bolster our commitment to employability, while innovative leadership and executive programmes alongside sterling integration with business experts helps our students gain key leadership positions both nationally and internationally. Career prospects in the biological sciences are exceptionally good. To some extent it depends on the specific topic, of course, but laboratory-based and especially quantitative skills and the proven innovation of a PhD or MPhil are highly sought after. Degrees are very much in demand, both in commercial science and public sector research and development (e.g. drug discovery and development, crop and animal improvements and welfare, sustainable agriculture and resource use, human nutrition and health, animal health, ecological management, food safety and technology, scientific communications, regulation, and many more fields).

Employment after the Course
Graduates have gone on to be professional research scientists, consultants, or hold technical and junior executive positions in commerce and government.

ENTRANCE REQUIREMENTS

Graduate
The minimum academic requirement for admission to a research degree programme is normally an Upper Second Class Honours degree in a relevant subject from a UK or ROI HE provider, or an equivalent qualification acceptable to the University. Further information can be obtained by contacting the School.

International Students

For information on international qualification equivalents, please check the specific information for your country.

English Language Requirements

Evidence of an IELTS* score of 6.5, with not less than 5.5 in any component, or an equivalent qualification acceptable to the University is required (*taken within the last 2 years).

International students wishing to apply to Queen’s University Belfast (and for whom English is not their first language), must be able to demonstrate their proficiency in English in order to benefit fully from their course of study or research. Non-EEA nationals must also satisfy UK Visas and Immigration (UKVI) immigration requirements for English language for visa purposes.

For more information on English Language requirements for EEA and non-EEA nationals see: www.qub.ac.uk/EnglishLanguageReqs.

If you need to improve your English language skills before you enter this degree programme, INTO Queen’s University Belfast offers a range of English language courses. These intensive and flexible courses are designed to improve your English ability for admission to this degree.

HOW TO APPLY

Apply using our online Postgraduate Applications Portal and follow the step-by-step instructions on how to apply.

Find a supervisor

If you’re interested in a particular project, we suggest you contact the relevant academic before you apply, to introduce yourself and ask questions.

To find a potential supervisor aligned with your area of interest, or if you are unsure of who to contact, look through the staff profiles linked here.

You might be asked to provide a short outline of your proposal to help us identify potential supervisors.