Postdoctoral Research Fellow – Translational Cancer Discovery Team and Paediatric Solid Tumour Biology and Therapeutics Team
Closing Date 03/03/2019, 23:55
Division Cancer Therapeutics
Team Translational Cancer Discovery
Vacancy Type Full time
Type of Contract Fixed Term
Length of Contract 2 years
Hours per Week 35
Salary Range £31,023 – £44,337
The Institute of Cancer Research, London, is one of the world’s most influential cancer research institutes, with an outstanding record of achievement dating back more than 100 years. We provided the first convincing evidence that DNA damage is the basic cause of cancer, laying the foundation for the now universally accepted idea that cancer is a genetic disease. Today, The Institute of Cancer Research (ICR) leads the world at isolating cancer-related genes and discovering new targeted drugs for personalised cancer treatment.
Under the leadership of our Chief Executive, Professor Paul Workman FRS, the ICR is ranked as the UK’s leading academic research centre. Together with our partner The Royal Marsden, we are rated in the top four cancer centres globally.
The ICR is committed to attracting, developing and retaining the best minds in the world to join us in our mission – to make the discoveries that defeat cancer.
We currently have a vacancy for a Postdoctoral Research Fellow to work on an exciting collaborative project in the team of Prof Raj Chopra, Director of the Cancer Research UK Cancer Therapeutics Unit. The Cancer Therapeutics Unit is a multidisciplinary ‘bench to bedside’ centre, dedicated to the discovery and development of novel therapeutics for the treatment of cancer. The Chopra team has world-leading expertise in drug development and novel technologies that can be applied to targeting of difficult-to-target cancer drivers, such as MYC.
Working together with the Paediatric Solid Tumour Biology and Therapeutics Team, which has a focus on paediatric cancers and expertise in modelling and targeting paediatric cancer drivers, such as MYC, our ultimate aim is to develop novel therapeutics targeting MYC oncogenic dependency states. The project will use cutting-edge technologies developed by Prof. Chopra and ICR medicinal chemists to develop novel small-molecule inhibitors of the MYC homologue MYCN, which is a major driver of paediatric brain and solid tumours with tissue specific expression restricted to tumour tissue.
Background and Approach
N-Myc is a definitive driver of several paediatric malignancies, including neuroblastoma, medulloblastoma and rhabdomyosarcoma. In neuroblastoma N-Myc amplification is one of the only molecular alterations used to risk-adapt therapy. In high-risk cases, amplification of N-Myc or overexpression is the most common finding, with up to 35% and additional 25% of patients affected, respectively. We have devoted much effort to identifying and targeting oncogenic functions and dependency states induced by aberrant expression of N-Myc, either through direct or indirect means. We have primarily used mass spectroscopy-immunoprecipitation to identify and drug key binding proteins which localise to the n-terminal MycBox1-conserved phosphodegron domain of N-Myc. We now wish to probe in more detail how key binding partners of N-Myc induce cellular dependency in neural cancers, apply novel screens to determine whether targeted elimination of these induces cellular lethality, senescence or differentiation. Degradation-based approaches will be used at scale to identify key partners of consequence for N-Myc that can be eliminated in order to selectively target N-Myc induced dependency.
The successful candidate will use novel E3-ligase modulators libraries to identify small-molecules that target critical partners that mediate oncogenic effects of N-Myc in transformed cells. They will use CRISPR/Cas9 and other gene-modification techniques to construct a panel of neuroblastoma cell lines with endogenous and exogenous expression of N-Myc, either mutated or wild-type at the MycBox1 phospho-residues T58 and S62, and containing surrogate markers of gene expression (RFP, GFP), to optimise high-throughput screening. These lines will also incorporate Tetracycline control elements to reversibly tune N-Myc expression.
There will be 3 deliverables to this project:
- Establish a panel of neuroblastoma cell lines with: a) regulatable (exogenously driven) N-Myc expression with or without surrogate imaging markers (eGFP, eRFP), b) stably transfected and regulatable shRNA to ablate N-Myc expression, in cell lines with N-Myc amplification and/or overexpression, and c) cell lines with endogenously driven N-Myc mutant for MycBox1 phosphoresidues (T58a/S62a). In addition, produce a set of cell lines stably transfected with N-Myc/eGFP fusions (exon3) with exogenous expression of N-Myc. Construct a N-Myc dTAG fusion in the above backgrounds. (time 6 months – 1yr)- year 1.
- Characterise biologic phenotypes of the cell panel to describe rates of cell cycle, changes in ploidy, oncogenic potential, cell proliferation, invasion, and N-Myc dependence in both 2D and 3D culture (neurosphere) conditions. Validate in vivo tumour forming potential using implanted systems (subQ, adrenal injection/orthotopic). (time 6 months – 1yr) – years 1 and 2.
- Perform E3-ligase modulators screens using methodology established in the Chopra laboratory, to identify key binding partners of N-Myc that mediate cellular dependency states.
The successful candidate will have substantial proven track record in the day to day running and successful conclusion of similar projects and have a demonstrable track record of experience in tissue culture, molecular biological techniques (PCR, RT-PCR, cloning, RNA, DNA and protein extraction, gene transfection etc) as well as 3D experimental tumour models. Knowledge of epigenetics, differentiation, apoptosis pathways and MYC biology though not essential would be desirable. The successful candidate will have a substantial track record of publishing in high ranking journals with at least two papers published as a first author.
This post will be for 2 years in the first instance, and benefits from a contributory defined benefit pension scheme and generous leave entitlement.
We consider all applications on merit and have a strong commitment to enhancing the diversity of our staff.