Mitigating radiation induced normal tissue toxicity by preventing senescence

This is project three of three.

Cancer Research UK (CRUK) have awarded funding to the Cancer Research UK City of London (CoL) Centre to create a CRUK Radiation Research Unit - RadNet. The unit will feature an ambitious research programme for radiation oncology and radiation biology. This network will accelerate the development of advanced radiotherapy techniques, challenging the boundaries of this mainstay treatment through world-first exploratory projects.

Via the Department of Medical Physics & Biomedical Engineering at UCL, CRUK CoL is inviting applications for 3 x 4-year studentships to be based across the CoL partners, with 3 x 2month research placements across the Centre.

This PhD studentship are an ideal opportunity for outstanding applicants with a scientific background who would like to carry out research projects in radiation biology, cancer and radiotherapy.

PhD students will follow the four-year CRUK CoL Centre PhD training programme and will be based in their primary supervisor’s research group. Students will register for their PhD at the primary supervisor’s university. All students will have a three-person thesis committee made up of Centre faculty that they will meet with regularly to discuss progress and receive guidance and advice. In addition to carrying out their PhD research and participating in core mandatory activities, including taking part in multi-disciplinary radiation research workshops and seminars and participating in CoL cohort-building activities, each trainee will have a ‘customised’ training programme, which will be developed with their supervisors taking into account the trainee’s background and PhD project needs. The ‘customised’ elements of the programme will include short research placements, and training in a vast range of scientific and transferable skills, accessible via the Centre partners and beyond. There will also be a strong emphasis on career mentoring and support.

Project Information
Technical advances in radiotherapy, including proton therapy, now permit highly targeted radiation to be delivered to tumour with significant normal tissue sparing. Radiation dose escalation has been postulated to improve intrathoracic malignancies, however clinical trials of dose escalation have been negative with a worse outcome in the dose escalation arm due to normal tissue toxicity (lung and heart). Furthermore, combining novel agents such as immunotherapy and targeted agents (ATR, ATM and other inhibitors) is challenging due to increased normal tissue toxicity.

Pathways implicated in normal tissue radiation injury are poorly understood. Senescence in normal-tissue stem cells, with accelerated ageing as a consequence of cancer treatment is an example of a potential pathway. Cellular senescence, which is a normal consequence of ageing, can result from DNA damage, oxidative stress, and chronic inflammation. Proton radiation appears to produce more cancer cell death through senescence when compared to X-rays [1].

Laboratory studies have confirmed the importance of senescence as a cause of radiation toxicity in irradiated lungs [2]. Other work has suggested that the factors elaborated by senescent cells may contribute to tumour progression [3] as senescent stem cells are unable to replenish themselves and injured cells; they may also contribute to disease through the secretion of proinflammatory factors. Preventing or clearing senescent cells has recently been shown to reduce the toxicity of radiation and to mitigate ageing-related illnesses in animal models [4, 5].

Our initial findings show that rapamycin – an approved compound for immunosuppression and advanced kidney carcinoma, when used in very small doses has a radioprotective effect for normal tissue which would have potential utility to reduce toxicities in radiotherapy treated cancers. One of the postulated mechanisms could be senescence prevention. The role of the immune system in normal toxicity prevention is not known.

More detailed information about the research project is available on request from Professor Maria Hawkins at [Email Address Removed].

Person Specification
Suitable candidates must have a minimum upper second-class Honours degree in an associated discipline, or an overseas qualification of an equivalent standard. They must also have knowledge of molecular biology, immunology and imaging. Experience of laboratory techniques such as tissue culture, FACS, confocal microscopy and in vivo experience would also be desirable.

For all studentships essential criteria include having potential to develop expertise in new areas of the subject; ability to develop understanding of complex problems and apply in-depth knowledge to address them; has potential for innovation and initiative, the ability to work both independently and as part of a team; and appropriate English language skills.

Eligibility
The closing date is 14th April 2020 and the anticipated start date is spring / summer 2020.
To apply for this studentship, you must submit only two documents:
1. Your full CV including a short summary (<500 words) detailing how your experience and ability matches the project and the person specification.
2. A single PDF file containing scans of two academic references, and the transcripts of your university degree(s) showing your unit/module marks.
These two documents should then be emailed to Michelle Craft, RadNet City of London project manager, at [Email Address Removed]. Please write ‘Application for PhD Studentship [number, Title]’ in the subject line of the email.