Postdoctoral Fellow
Contact term:
• This is a full-time fixed term position for 4 years on Crick Terms & Conditions of employment
The Research Group
Julian Downward’s laboratory (Oncogene Biology) investigates the mechanisms by which mutant oncogenes drive the formation of tumours and how understanding this better can promote more effective approaches to treating cancer in the clinic. We particularly focus on the RAS family of oncogenes, which are the most frequently mutated oncogenic drivers in human cancer. We are seeking a talented and motivated postdoctoral research fellow with experience in tumour immunology to join our group.
The first generation of clinical KRAS inhibitors, G12C selective sotorasib and adagrasib, are seriously compromised by the rapid development of drug resistance in clinical use for lung cancer. We hypothesise that the killing of drug sensitive tumor cells could promote an immune response against drug resistant subclones that share similar antigens. We have adapted our mouse lung cancer models described above to study this potential bystander killing, utilizing mixed populations of drug sensitive G12C KRAS mutant lung cancer cells with otherwise isogenic G12D KRAS drug resistant cells, or non-engineered drug resistant populations that have arisen under selective pressure in vivo. The cell populations are tagged and barcoded. They will be used to address the following issues:
• What constrains immune-mediated bystander killing of G12C inhibitor drug resistant tumor cells? We will use multiplexed imaging and spatial transcriptomics to identify responses to G12C inhibitor in drug sensitive tumor cells, in drug resistant tumor cells and in non-tumor cells of the tumor microenvironment. Preliminary data from more narrow interrogation of the tumor response using imaging mass cytometry, or single cell RNA-Seq lacking spatial component, suggest a number of candidate immunosuppressive mechanisms, including regulatory T cells, extracellular adenosine signaling, TGFb and CD47/SIRPa.
• Would rational combination of G12C inhibitor with immune therapies targeting the pathways implicated by the above work provide improved response of the drug resistant tumor cell subpopulation, as well as the drug sensitive bulk population?
• How would these combinations compare with standard immune checkpoint blockade combinations such as those involving PD1 or CTLA4 blockade, and also SHP2 inhibition, a therapy acting in part on cells of the tumor immune microenvironment, particularly immunosuppressive myeloid cells?
• Once optimal combination strategies have been identified to eliminate drug resistant subpopulations, what would be the limits of the bystander killing effect in terms of drug resistant cell fraction and overall tumor size? Does treatment sequencing impact the effectiveness of the combination? In mice that have rejected tumors, is immune memory established and for how long?
• Findings from the mouse models will be compared to publicly available datasets from human lung cancer to verify, or otherwise, the presence of immune suppressive features in the tumor microenvironment that would indicate the potential for similar responses in human tumors. Beyond the scope of the proposed project, these would form the basis for clinical trials of selected combinations, initially in a neo-adjuvant setting with analysis of the immune response in drug treated tissue samples.
We hope that this work will allow the identification of therapeutic approaches to reverse the shielding of the KRAS mutant lung tumours from the immune system and how best to eliminate the acquisition of drug resistance by minor cell populations in advanced tumours to enable effective long-term treatment and ultimately cure of this disease.
Information about the work of the laboratory can be found at the links below:
http://crick.ac.uk/research/a-z-researchers/researchers-d-j/julian-downward/ http://scholar.google.co.uk/citations?user=9bDwgogAAAAJ&hl=en https://orcid.org/0000-0002-2331-4729Key experience and competencies
Qualifications, experience and competencies
• PhD in relevant subject area or in the final stages of PhD submission
• Good knowledge and experience in cancer biology, molecular cell biology and immunology
• Technical expertise in tumour immunology, such as immune phenotyping by FACS, single cell sequencing, multiplexed spatial imaging or mass cytometry
• Experience in the use of mouse models in cancer or immunology research
• Experience in the use of bioinformatics to analyse large biological datasets
• Track record of writing papers as evidenced by publications or submitted manuscripts in refereed journals
• Evidence of data presentation at scientific meetings
• Ability to work with minimal supervision using own initiative to organise and prioritise own work
• Ability to define and solve research questions
• Pro-active in innovation and problem solving
• Experience of experimental design
Postdoctoral Fellows are expected to lead their own projects, contribute to other projects on a collaborative basis (both in the lab and with external collaborators) and guide PhD students in their research. The ability to work in a team is essential.
The Crick will support successful applicants in applying for a work permit or visa to work in the United Kingdom if required. All offers of employment are subject to successful security screening.
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