Job Opportunities

Supervisor(s): Professor James Brenton

Deadline for application: 31st October 2024

Course start date: 1st October 2025

Overview

Professor James Brenton wishes to recruit a student to work on the project entitled: "Modelling new therapeutic approaches for neoadjuvant treatment of high grade serous ovarian carcinoma".

For further information about the research group, including their most recent publications, please visit our website at: https://www.cruk.cam.ac.uk/research-groups/brenton-group/

This is a unique opportunity for PhD study in the world-leading Cancer Research UK Cambridge Institute (CRUK CI), to start a research career in an environment committed to training outstanding cancer research scientists of the future.

The Institute's particular strengths are in genomics, computational biology and imaging; and significant research effort is currently devoted to cancers arising in the breast, pancreas, brain, and colon. Our Core Facilities provide researchers with access to state-of-the-art equipment, in-house expertise and training. Scientists at CRUK CI aim to understand the fundamental biology of cancer and translate these findings into the clinic to benefit patients.

There are around 100 postgraduate students at the Cambridge Institute, who play a vital and pivotal role in its continuing success. We are committed to providing an inclusive and supportive working environment that fosters intellectual curiosity and scientific excellence.

If you are interested in finding out more about our groundbreaking scientific research, please visit our website at https://www.cruk.cam.ac.uk/

Project details

High-grade serous ovarian carcinoma (HGSC) is molecularly characterised by extreme chromosomal instability which presents a major barrier to personalized therapy. Most patients with HGSC in the UK receive neoadjuvant chemotherapy but this has particularly poor outcome because of: (1) suboptimal therapeutic effects and (2) rapid acquisition of drug resistance. The major need is to develop new clinical trials with agents that minimize these deleterious effects. We are using integrative approaches to address these problems using genomic and functional characterization of clinical trial samples together with patient-derived organoid and xenograft (PDX) models. We have developed whole genome sequencing (WGS) methods that provide copy number signatures that classify HGSC based on mutational processes. With these methods we have generated large WGS data sets that are being used to design clinically relevant immunocompetent mouse models using in vivo CRISPR recombination.

The aim of the project is to develop new therapeutic approaches for neoadjuvant therapy of BRCA1 mutated HGSC. These patients have adverse outcomes despite initial response to platinum-based chemotherapy and PARP maintenance treatment. The project will focus on modifiers of chemotherapy induced senescence and combination therapy with new drugs targeting DNA damage response. The experimental approach will combine cell fate analysis using in vitro and in vivo lineage tracing using existing PDX and CRISPR engineered models that can evaluate coincident immunological responses. Pharmacodynamic effects on the DNA damage response pathways will be measured using single cell technologies, including CyTOF and imaging mass cytometry of pre-clinical models and patient samples. From this work we expect to deeply characterize tumour cell clonal evolution and adaptations to these treatment combinations which will guide the design of new clinical trials for HGSC.

The successful candidate can expect to develop innovative skills in both computational and experimental approaches. The project will be closely aligned with two post-doctoral workers focusing on mouse models and one computational post-doctoral worker with extensive WGS experience.

References/further reading (optional)

• Vias M, Morrill Gavarró L, Sauer CM, Sanders DA, Piskorz AM, Couturier D-L, Ballereau S, Hernando B, Schneider MP, Hall J, Correia-Martins F, Markowetz F, Macintyre G, Brenton JD. 2023. High-grade serous ovarian carcinoma organoids as models of chromosomal instability. Elife 12:e83867. doi:10.7554/eLife.83867.
• Crispin-Ortuzar M, Woitek R, Reinius MAV, Moore E, Beer L, Bura V, Rundo L, McCague C, Ursprung S, Escudero Sanchez L, Martin-Gonzalez P, Mouliere F, Chandrananda D, Morris J, Goranova T, Piskorz AM, Singh N, Sahdev A, Pintican R, Zerunian M, Rosenfeld N, Addley H, Jimenez-Linan M, Markowetz F, Sala E, Brenton JD. 2023. Integrated radiogenomics models predict response to neoadjuvant chemotherapy in high grade serous ovarian cancer. Nat Commun 14:6756. doi:10.1038/s41467-023-41820-7.
• Sauer CM, Hall JA, Couturier D-L, Bradley T, Piskorz AM, Griffiths J, Sawle A, Eldridge MD, Smith P, Hosking K, Reinius MAV, Morrill Gavarró L, Mes-Masson A-M, Ennis D, Millan D, Hoyle A, McNeish IA, Jimenez-Linan M, Martins FC, Tischer J, Vias M, Brenton JD. 2023. Molecular landscape and functional characterization of centrosome amplification in ovarian cancer. Nat Commun 14:6505. doi:10.1038/s41467-023-41840-3.
• Sauer CM, Heider K, Belic J, Boyle SE, Hall JA, Couturier D-L, An A, Vijayaraghavan A, Reinius MA, Hosking K, Vias M, Rosenfeld N, Brenton JD. 2022. Longitudinal monitoring of disease burden and response using ctDNA from dried blood spots in xenograft models. EMBO Mol Med 14:e15729. doi:10.15252/emmm.202215729.
• Smith P, Bradley T, Gavarró LM, Goranova T, Ennis DP, Mirza HB, De Silva D, Piskorz AM, Sauer C, Al-Khalidi S, Funingana I-G, Reinius MAV, Giannone G, Lewsley L-A, Stobo J, McQueen J, Bryson G, Eldridge M, BriTROC Investigators, Macintyre G, Markowetz F, Brenton JD, McNeish IA. 2023. The copy number and mutational landscape of recurrent ovarian high-grade serous carcinoma. Nat Commun 14:4387. doi:10.1038/s41467-023-39867-7.
• Macintyre G, Goranova TE, De Silva D, Ennis D, Piskorz AM, Eldridge M, Sie D, Lewsley L-A, Hanif A, Wilson C, Dowson S, Glasspool RM, Lockley M, Brockbank E, Montes A, Walther A, Sundar S, Edmondson R, Hall GD, Clamp A, Gourley C, Hall M, Fotopoulou C, Gabra H, Paul J, Supernat A, Millan D, Hoyle A, Bryson G, Nourse C, Mincarelli L, Sanchez LN, Ylstra B, Jimenez-Linan M, Moore L, Hofmann O, Markowetz F, McNeish IA, Brenton JD. 2018. Copy number signatures and mutational processes in ovarian carcinoma. Nat Genet 50:1262-1270. doi:10.1038/s41588-018-0179-8.

Preferred skills/knowledge

- Required: Clear potential for development of strong laboratory and computational skills. Strong critical thinking, organization, team player and emotional intelligence skills are required. Demonstrable evidence showing self-starting and self-motivational skills.

- Advantageous: Previous experience of projects involving ovarian carcinoma or pre-clinical mouse models.

Funding

This four-year studentship is funded by Cancer Research UK Cambridge Institute and includes full funding for University fees and, in addition, a stipend currently of £21,000 per annum for four years.

Eligibility

We welcome applications from both UK and overseas students.

Applications are invited from recent graduates or final-year undergraduates who hold or expect to gain a First/Upper Second Class degree (or equivalent) in a relevant subject from any recognised university worldwide.

Applicants with relevant research experience, gained through Master's study or while working in a laboratory, are strongly encouraged to apply.

How to apply

Please apply via the University Applicant Portal. For further information about the course and to access the Applicant Portal, visit:
https://www.postgraduate.study.cam.ac.uk/courses/directory/cvcrpdmsc You should select to commence study in Michaelmas Term 2025 (October 2025).

Additional information

To complete your online application, you will need to answer/provide the following:

- Choice of project and supervisor

Please ensure that you name the project (with reference code) and supervisor, where indicated. You are permitted to apply for up to three projects.

Course-specific questions

• You will be asked to give details of your Research Experience (up to 2,500 characters).
• Your Statement of Interest (up to 2,500 characters) should explain why you wish to be considered for the studentship and what qualities and experience you will bring to the role.

Supporting documents

Applicants will be asked to provide:

• Academic transcripts.
• Evidence of competence in English (if appropriate).
• Details of two academic referees.
• CV/resume.

The University actively supports equality, diversity and inclusion and encourages applications from all sections of society.

The University has a responsibility to ensure that all employees are eligible to live and work in the UK.