About the Project
This Ph.D. studentship will be hosted in the Halim Lab in the CRUK Cambridge Institute (https://www.cruk.cam.ac.uk/research-groups/halim-group), and co-supervised by Dr Tim Halim (CRUK Cambridge Institute), Professor Ashok Venkitaraman (Cancer Science Institute of Singapore) and Mr. Siong-Seng Liau (University Department of Surgery, Addenbrooke’s Hospital). The translational component of the research will be supported by the Cambridge Pancreatic Cancer Centre and the Hepatopancreatobiliary (HPB) Surgical Unit at Addenbrooke’s Hospital.
Project details
Recent studies characterising the human PDAC genome indicate that about 15-20% harbour pathogenic mutations affecting a small group of functionally-related genes including BRCA2 and PALB2, which are essential for the repair of DNA double-strand breaks (DSBs) by homologous DNA recombination (HDR) (reviewed in Venkitaraman, 2014). Despite frequently being effective in HDR-deficient cancers in other tissue types, poly-ADP ribose polymerase 1 inhibitors (PARP1i) have a poor impact on HDR-deficient PDACs, for reasons that remain unclear. This underscores the need for alternative approaches. Reactivation of the immune response against cancer using therapeutic antibodies against inhibitory ligands such as CTLA4 or PD1/PDL1 may be a potentially transformative treatment approach in DNA repair-deficient PDAC. But how HDR deficiency affects the evolution of PDAC, and its response to immunotherapy, have not yet been fully determined. Moreover, immunomodulatory targets for HDR-deficient PDAC alternative to anti-CTLA4/PD1/PDL1 have not yet been characterized.
Work in this theme will deploy novel genetically-engineered murine models (GEMMs) of HDR-defective PDAC that recapitulates KRAS-driven carcinogenesis associated with pathogenic human mutations in BRCA2 (Skoulidis et al., 2010) or PALB2 (Liau, Venkitaraman et al., in preparation). Such mutations are amongst the most frequent that cause HDR-defective PDAC, and serve as a powerful model for a significant fraction of pancreatic cancers. Foundational work in this theme already demonstrates that these models faithfully recapitulate features of HDR-deficient PDAC carcinogenesis in humans, and that tumours that arise in this setting exhibit evidence of immune evasion during their evolution. Thus, our preliminary work leading up to this proposal suggests a novel role for the control of immune gene expression by DNA methylation as a mechanism underlying immune evasion in HDR-deficient PDA. We now propose to validate the proposed mechanism, and test approaches to reverse it for PDA therapy.
Qualifications/skills
We expect the applicant to be highly motivated with a strong desire to translate basic science findings into clinical applications. Skills will be gained in molecular biology of cancer using cell-line based in vitro models of pancreatic cancer with HRD. The programme will offer unique access to genetically engineered mouse models of HRD pancreatic cancer (specifically PALB2- and BRCA2-deficiency), including access to biorepository of pancreatic cancers from these models. Access will also be provided to human samples of pancreatic cancer at various stages of clinical disease.
How to apply:
All applications need to be made using the University Applicant Portal. Please visit: https://www.graduate.study.cam.ac.uk/courses/directory/cvcrpdmsc for further information about the course and to access the applicant portal.
Please indicate that you wish to be considered for Cambridge Trust funding.
To complete your on-line application, you need to provide the following:
Reference Request: The names and contact details of two academic referees who have agreed to act on your behalf.
Research: If you wish to be considered for more than one studentship in CRUK CI, please enter the names of all of the supervisors you wish to consider your application in the ’Research summary’ text box. If you only wish your application to be considered by a single supervisor, then please enter their name in the ’Research Supervisor’ text box. Please describe your past ’Research experience’ in the appropriate text box.
Course Specific Questions: Your statement of interest (limit of 2,500 characters) should explain why you wish to be considered for the studentship and which qualities and experience you will bring to the role. Please also state how you learned of the studentship.
Supporting Documents: Please upload your CV (PDF file), which should include a list of the examinations taken at undergraduate level and if possible, your examination results.
Funding Notes
Funding:
This studentship is funded by the Pancreatic Cancer UK Future Leaders Academy that includes full funding for University and College fees, a stipend of £19,000 per annum over a period of 4 years, and funding for consumables.
Eligibility
No nationality restrictions apply to this studentship. Applications are invited from recent graduates or final year undergraduates who hold or expect to gain a first/upper second class degree (or equivalent) or Master's degree in a relevant subject from any recognised university worldwide.
References
Janssen B, Bellis S, Koller T, Tischowitz M, Liau S-S (2020). A systematic review of predicted pathogenic PALB2 variants: an analysis of mutational overlap between epithelial cancers. J Hum Genet 2020; 65 (2).
Cassidy LD, Liau SS, Venkitaraman AR (2014). Chromosome instability and carcinogenesis: insights from murine models of human pancreatic cancer associated with BRCA2 inactivation. Mol Oncol 2014; 8(2): 161-8.
Liau SS, Monk S, Cooper D, Venkitaraman AR (2020). Genome instability from homologous repair deficiency promotes immune evasion. In preparation.
Liau SS, Monk S, Cooper D, Venkitaraman AR (2020). Loss of heterozygosity of Palb2 gene cooperates with K-ras and p53 mutations to promote pancreatic tumourigenesis via intraductal papillary mucinous neoplasms. In preparation.
Venkitaraman AR (2014). Cancer suppression by the chromosome custodians, BRCA1 and BRCA2. Science 2014; 343(6178):1470-5
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