Job offer in london Postdoctoral Training Fellow Oncogene Biology – The Francis Crick Institute



Fixed-term (4 years), Full time

An exciting role has come up to be a part of a pioneering biomedical research institute, dedicated to innovation and science. We are seeking a talented and motivated postdoctoral research fellow with experience in tumour immunology to join the research group led by Julian Downward. The Oncogene Biology laboratory investigates the mechanisms by which mutant oncogenes drive the transformation of cells to a malignant cancerous state. We particularly focus on the RAS family of oncogenes, which are the most frequently mutated oncogenic drivers in human cancer. Despite enormous research efforts, at present there are still no effective therapies against the 20% of human cancers that are caused by activating mutations in RAS oncogenes.

Project Description

Despite huge advances in our understanding of the mechanisms involved in the subversion of cellular growth regulation in cancer, therapeutic agents targeting growth regulatory pathways have often proved disappointing in the clinic for the treatment of advanced cancers. Even agents that are initially highly effective, such as EGFR or BRAF inhibitors in lung cancer or melanoma bearing activating mutations in these oncogenes, have failed to provide long-term benefit due to the evolution of drug resistance. In order to move beyond treatments that only delay advanced cancers for a few months or, at best, years, we need to understand how to eradicate tumour cells completely, not leaving minor populations that go on to develop drug resistance and cause disease relapse. A very interesting area of investigation in this regard is that of immunotherapy. Tumours have to find ways to avoid recognition as foreign by the immune system, and recent clinical trials have achieved remarkable response rates using immune checkpoint inhibitors as immunotherapies in certain advanced cancers. This has illustrated how efficiently immune surveillance is suppressed locally by tumours and how powerful the intrinsic anti-tumour response can be if this suppression can be overcome. However, response rates to immunotherapies are highly variable and it is entirely unclear how these therapies can be combined to best effect with existing treatments.

Recent work in our lab has established mechanisms whereby RAS oncogenes promote the ability of tumours to evade the immune system by promoting the expression of immune checkpoint proteins (Coelho et al. in press). We are also interested in the possibility that mutant RAS proteins themselves may be seen as foreign by the immune system and could form the basis for the development of potential vaccines against RAS mutant cancers. Recently, Tran et al (N Engl J Med 375;23, 2016) reported the identification and therapeutic use of CD8+ T cells recognising G12D mutant KRAS in a patient with metastatic colon cancer. In this project we aim to develop dendritic cell-targeted vaccines against oncogenic KRAS mutant peptides and test them in a number of mouse cancer models. Dendritic cell targeting will initially be achieved through coupling of KRAS mutant peptides to an antibody against the dendritic cell surface receptor protein, DNGR-1. Mouse cancer models will include both carcinogen-induced models where specific mutations are induced in Kras and also syngeneic transplantation models using mouse cancer cells with relevant Kras mutations. The potential of such vaccination strategies will be tested in both a therapeutic and a prophylactic setting, using models of Kras mutant pancreatic, lung and colon cancers. Such work if successful could provide proof of concept to move to implementation in a clinical setting in human patients. The very high KRAS mutation rates in pancreatic cancer (95%) would make this an attractive setting for the use of a prophylactic vaccine.

Information about the work of the laboratory as a whole can be found at the following links: http://crick.ac.uk/research/a-z-researchers/researchers-d-j/julian-downward/ http://scholar.google.co.uk/citations?user=9bDwgogAAAAJ&hl=en https://en.wikipedia.org/wiki/Julian_Downward

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