About the Project
The Pharmacology and Drug Development Group (PDDG) in the CRUK Cambridge Institute aims to develop improved therapeutic approaches for the treatment of patients with pancreatic ductal adenocarcinoma (PDAC), which is one of the most lethal human cancers and a priority cancer for the Cambridge Cancer Centre. A major reason for the poor prognosis associated with this disease is the ineffectiveness of therapies available for patients with advanced disease. It has been suggested that this is due to the dense fibrotic stroma in PDAC, which appears to direct effects on the chemosensitivity of tumour cells and also suppress anti-tumour immune responses.
The CRUK CI and Pancreatic Cancer UK are offering a PhD studentship aimed at investigating novel therapeutic strategies that target the complex pancreatic tumour microenvironment as well as the tumour cells, either acting independently to inhibit tumour growth or enhancing the effectiveness of existing therapies (e.g. chemotherapy and radiotherapy).
This project will investigate the effectiveness of novel combinations of therapeutic agents in PDAC using both in vitro and in vivo approaches. PDAC model systems established in the lab include cell lines and co-cultures in vitro and the KPC genetically engineered mouse (GEM) model [1] of this disease. Studies investigating mechanisms of drug resistance are currently in progress and this new project will explore candidate signaling pathways as therapeutic targets. The effectiveness of novel combinations will be quantified to identify synergy and mechanisms will be investigated using analysis methods that we have used previously [2,3,4,5].
Analysis of pharmacological responses may include methods such as cell viability, Western blotting and immunofluorescence, and more global methods such as RNA-Seq and/or proteomics.
Candidate molecular effectors of resistance will be investigated by inhibition using siRNA and/or chemical inhibitors. Novel targeted agents will be obtained from our academic and commercial collaborators.
Effective combinations will then be validated in vivo to determine whether dose-‐dependent efficacy can be observed. In vivo mouse models of PDAC will include the KPC mouse, PDAC xenografts and syngeneic immunocompetent grafts. Efficacy will be measured by assessment of tumour growth (which may include novel non-‐invasive imaging techniques, in collaboration with other groups in the CI (Brindle, Bohndiek) and by assessment of pharmacodynamic (molecular) endpoints. Promising agents may also be tested in vivo in combination with immunotherapies [6,7].
This project forms part of the broader pancreatic cancer therapy research programme in the PDDG, which aims to integrate and optimise the pre-‐clinical development and "science-‐led" clinical application of novel therapies, including "first into man" (phase I) and associated studies. Therefore, the successful student will have an identified, independent project, but will benefit from support and guidance from an established group (e.g. experience in the use of the mouse models and bespoke PK assays, developed in house to assess drug uptake and pharmacokinetics [8, 9]), in addition to the support of the extensive core facilities and opportunities for collaboration in the CRUK CI.
The successful applicant is likely to hold a top class undergraduate degree in a relevant subject and/or a Masters degree from a prestigious university. Some relevant hands-on experimental research experience is preferred, which may have been obtained during undergraduate degree projects, a Masters’ degree or summer internships. Applicants should have the ability to work independently while accepting advice and supervision, and the ability to work collaboratively with colleagues as part of a team. The successful applicant will enjoy working in a competitive environment and will show evidence of a commitment to cancer research.
Funding Notes
This studentship is funded by Cancer Research UK and includes full funding for University and College fees and in addition, a stipend of £19,000 per annum, initially for 3 years, with funding for a further year possible as required.
No nationality restrictions apply to this Cancer Research UK funded 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) in a relevant subject from any recognised university worldwide.
References
1. Hingorani SR, et al., Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell, 2005, 7(5): p. 469-‐83.
2. Lin Y, et al., Paclitaxel and CYC3, an aurora kinase A inhibitor, synergise in
pancreatic cancer cells but not bone marrow precursor cells. Br J Cancer, 2012, 107(10): p. 1692-‐701.
3. Koh SB, et al., CHK1 Inhibition Synergizes with Gemcitabine Initially by Destabilizing the DNA Replication Apparatus. Cancer Res., 2015, 75(17): p. 3583-95.
4. Di Veroli GY, et al., Combenefit: an interactive platform for the analysis and visualization of drug combinations. Bioinformatics, 2016, 32(18): p. 2866-8.
5. Koh SB, et al., A quantitative FastFUCCI assay defines cell cycle dynamics at a single-cell level. J Cell Sci., 2017, 130(2): p. 512-20.
6. Feig C, et al., Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A., 2013, 110(50): p. 20212-7.
7. Flint TR, et al., Tumor-Induced IL-6 Reprograms Host Metabolism to Suppress Anti-tumor Immunity. Cell Metab., 2016, 24(5): p. 672-84.
8. Courtin A, et al., Anti-‐tumour efficacy of capecitabine in a genetically engineered mouse model of pancreatic cancer. PLoS One, 2013, 8(6): e67330.
9. Bapiro TE, et al., Gemcitabine diphosphate choline is a major metabolite linked to the Kennedy pathway in pancreatic cancer models in vivo. Br J Cancer, 2014, 111(2): p. 318-25
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