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PhD studentship: Population dynamics of adaptive mutagenesis & immune selection in colorectal cancer

This PhD project aims to investigate the population dynamics of microsatellite diversity non-invasively at high depth in patients undergoing checkpoint inhibitor treatment (NEOPRISM-CRC trial).

  • Primary supervisor Dr Marnix Jansen
  • Secondary supervisor Dr Kai-Keen Shiu

APPLICATIONS CLOSED (Monday 11 January 2021 17:00 (GMT)


Project

Full title: Population dynamics of adaptive mutagenesis and immune selection during immune checkpoint blockade in colorectal cancer (NEOPRISM-CRC trial)

Recent years have seen a true revolution in the treatment of cancer. A new class of drugs, called checkpoint inhibitors, has shown impressive results in the treatment of a range of cancers, including cancers deficient in DNA mismatch repair. These checkpoint inhibitors target the cellular receptors that cancer cells use to masquerade as normal cells; blocking these immune-evasion receptors unleashes the patient’s immune system and kills the tumour cells with great efficacy. However, these new drugs have not been equally effective in every treated patient. To harvest the full potential of this powerful new class of drugs, we urgently need resources to study how immune selection drives treatment failure in mismatch repair deficient cancer, and compare responders to non-responders.

Forecasting treatment response and tumour evolution through non-invasive disease monitoring is a key goal in cancer medicine. We have investigated the evolution of immune adaptation in mismatch repair-deficient cancer and discovered a core family of conserved genetic switches that drive immune-evasion. These switches act like a molecular gear box to dramatically accelerate mutation rate and spawn countless novel clonal lineages in response to immune selection. This PhD project aims to investigate the population dynamics of microsatellite diversity non-invasively at high depth in patients undergoing checkpoint inhibitor treatment (NEOPRISM-CRC trial). We want to trace in detail the evolutionary trajectories taken by tumour cell lineages as they clonally diversify and adapt to immune selection. Population dynamics of microsatellite diversity in peripheral blood during immune checkpoint inhibition will be correlated to tumour clonal complexity, neo-antigen burden, and mutation bias in tissue samples taken before and after immune checkpoint inhibition. This work will directly sample the evolution of immune selection during treatment and generate markers predictive of treatment response for patient benefit. 

The ideal candidate combines prior experience in evolutionary cancer biology and relevant laboratory techniques with exposure to theoretical population genetics. Previous experience in stochastic modelling is welcomed, but a strong drive to pursue a scientific career and work at the interdisciplinary frontier between evolutionary cancer genetics, computational genomics, and clinical medicine is equally important.

Interested candidates are urged to get in touch (m.jansen@ucl.ac.uk)
 

Person specification

Essential 

  • This multidisciplinary work bridges laboratory science, computational genomics and theoretical modelling. Models can be tested in ongoing clinical trials at UCLH NHS Trust of patients with microsatellite instable cancer undergoing checkpoint inhibitor treatment. The ideal candidate combines a wet laboratory background with experience in computational genomics. 
  • We are looking for a talented PhD candidate with or expecting at least an upper second class honours degree in a relevant subject (or an overseas qualification of an equivalent standard) and a strong interest in evolutionary cancer biology and/or immune-oncology are required for this project. 
  • The studentship will provide advanced training in cutting edge next generation sequencing pipelines, together with the necessary high dimensional data analysis context to analyse this data.
  • Ability to develop understanding of complex problems and apply in-depth knowledge to address them.
  • Potential to develop expertise in new areas of the subject.
  • Potential for innovation and initiative, and evidence of an ability to work independently.
  • Effective communication skills in both written and spoken English and a desire to work in a multidisciplinary team environment.

 

Desirable 

  • Relevant laboratory research experience in evolutionary cancer studies.
  • Experience with quantitative population genetics approaches and computational modelling may prove advantageous.

 

Students will also need to qualify as UK/EU fee payers and meet UCL general admissions criteria

Duties and responsibilities

Research 

  • To apply highly specialist scientific skills and expertise to lead in the delivery of high quality research and the preparation of high-impact research publications.
  • To keep abreast of current developments in this research area.
  • To report research progress to the supervisory team, the Cancer Institute, and at scientific conferences and meetings.
  • To work with other Scientists within the team as necessary.
  •  To work safely by adhering to all University policies and practices, including preparing and following laboratory risk assessments, and complying with Health and Safety policies, ethical approval processes and Human Tissue Act guidelines.

Analytical and Judgement Skills 

  • To demonstrate a high-level of technical and analytical skill to resolve highly complex scenarios, requiring analysis, interpretation and expert judgement to find the most appropriate solutions.
  • To identify, interpret and integrate information from a wide variety of sources, and critically evaluate the quality and assumptions of these data.
  • To show initiative and the ability to make decisions in areas where no previous work has been undertaken.
  • To show awareness of your own developmental needs and undertake appropriate training where appropriate.
  • To comply with professional codes of conduct.

 

Research environment

The UCL Cancer Institute is a state-of-the-art institute to consolidate cancer research at UCL and promote links with our partner teaching hospitals, in order to support excellence in basic and translational studies. The Institute draws together talented scientists who are working together to translate research discoveries into developing kinder, more effective therapies for cancer patients. It is a Cancer Research UK and Experimental Cancer Medicine Centre, and contains approximately 580 staff, including 80 PhD and MD (Res) students and 30-40 MSc students. Core facilities within the Institute include: Genomics Facility (gene expression microarrays); Proteomics Facility; Imaging and Cell Sorting (confocal, time-lapsed microscopy, MoFlo FACS); Pathology Suite (laser capture microdissection, tissue arrays); Experimental Imaging (with UCL Institute of Child Health); and Transgenesis.


Application

APPLICATIONS CLOSED (Monday 11 January 2021 17:00 (GMT)

Students will need to qualify as UK/EU fee payers and meet UCL general admissions criteriaThis studentship is subject to confirmation of funding from CRUK.

To apply for this studentship, you must submit only three 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
  3. An equal opportunities monitoring form (Word download). This form will be separated from your application before it is forwarded to shortlisters. By submitting this form you are giving us consent to use the data contained for quality and monitoring purposes. Data will be anonymised.  . 

These three documents should then be emailed to ci.scholarships@ucl.ac.uk. Please write 'CRUK 2006 Jansen' in the subject line of the email. 

APPLICATIONS CLOSED (Monday 11 January 2021 17:00 (GMT)