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Exploring the differential effect of low rapamycin concentration on normal tissue toxicity (lung, heart, marrow) in vitro and in vivo model versus cancer when exposed to X-rays or protons.
- Primary supervisor: Professor Maria Hawkins, UCL Dept. of Medical Physics and Biomedical Engineering
- Secondary supervisor: Dr Ivana Bjedov, UCL Cancer Institute
Candidates will need to qualify as UK/EU fee payers.
Closing date: Tuesday 14 April 2020
Project description.
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.
The objectives would be:
(i) To explore the differential effect of low rapamycin concentration on normal tissue toxicity (lung, heart, marrow) in vitro and in vivo model versus cancer when exposed to X-rays or protons. This will help establish universality of rapamycin mediated radioprotection/mitigation in different cancers and stages of disease.
(ii) To measure ‘omics’ changes (such as transcriptomics) and explore role of senescence in both normal tissue and tumour resistance to radiation. We will focus on the role of senescence in rapamycin-mediated radioprotection, as senescence has a known role in radiation toxicity and can be modulated by rapamycin. Transcriptomic analysis will help characterise senescence signature and it will elucidate other possible radioprotective mechanisms, such as rapamycin effect on reactive oxygen species, DNA repair, and immunity, which will then be tested epistatically in vitro.
(iii) To perform whole genome sequencing on irradiated rapamycin treated and irradiated rapamycin non-treated normal tissue. This will help evaluate rapamycin effect on genome stability upon irradiation and will further elucidate rapamycin-mediated radioprotection mechanism from mutation signature analyses.
Insight into radioprotective mechanism of rapamycin could be rapidly translated with early phase proof of concept radiotherapy clinical trials with the ultimate goal to provide better anti-cancer radiation treatment by reducing toxicities, thereby benefiting patients.
During the project the student will develop skills in a wide range of molecular and cellular biological techniques, including extensive microscopy work. The successful candidate will benefit from inter-disciplinary training in DNA damage response and repair, radiation biology and physics, cell signalling, genomics and bioinformatics. Successful applicant will attend UCL training in scientific writing, communication and presenting, microscopy data analysis and image processing, bioinformatics resources and application.
CoL Centre RadNet students will follow the CRUK CoL Centre PhD training programme. In addition to carrying out their PhD research and participating in core mandatory 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.
Mandatory training activities will include an induction programme to introduce trainees to doing a PhD, the Centre and its science, its infrastructure cores, experiment design, research integrity, and science project management. In addition, RadNet students will take part in multi-disciplinary radiation research workshops and seminars and participate in CoL cohort-building activities, including giving talks (as part of an annual Centre trainee meetings and Centre symposia), attending meetings, networking events, and seminars.
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.
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.
- 1. Wang, L., et al., Proton versus photon radiation-induced cell death in head and neck cancer cells. Head Neck, 2019. 41(1): p. 46-55.
- 2. Citrin, D.E., et al., Role of type II pneumocyte senescence in radiation-induced lung fibrosis. J Natl Cancer Inst, 2013. 105(19): p. 1474-84.
- 3. Pribluda, A., et al., A senescence-inflammatory switch from cancer-inhibitory to cancer-promoting mechanism. Cancer Cell, 2013. 24(2): p. 242-56.
- 4. Chung, E.J., et al., Truncated Plasminogen Activator Inhibitor-1 Protein Protects From Pulmonary Fibrosis Mediated by Irradiation in a Murine Model. Int J Radiat Oncol Biol Phys, 2016. 94(5): p. 1163-72.
- 5. Chung, E.J., et al., Mammalian Target of Rapamycin Inhibition With Rapamycin Mitigates Radiation-Induced Pulmonary Fibrosis in a Murine Model. Int J Radiat Oncol Biol Phys, 2016. 96(4): p. 857-866.
More detailed information about the research project is available on request from Professor Maria Hawkins at m.hawkins@ucl.ac.uk
- 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. Other essential criteria includes 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
Funding and application
Funding will be for 4 years, with a tax free stipend of £21,000 per year plus UK/EU-level university fees. Due to funding body restrictions, only UK / EU nationals are eligible to apply for this programme.
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 m.tu@ucl.ac.uk.
Please write ‘Mitigating radiation induced normal tissue toxicity by preventing senescence’ in the subject line of the email.
