PhD Studentship in Cancer Studies (PhD Studentship)
Reference Number: R2260
Project title: Elucidation of the role of transforming growth factor beta signalling in cancer stem cell drug resistance
Many cancers have hijacked growth factor receptors and or downstream signalling components through mutations that render the pathway constantly active and so drive cancer cells division. Over the last decade, drugs have been introduced that simultaneously inhibit multiple growth factor pathways (such as tyrosine kinase receptor inhibitors), single pathways (vascular endothelial growth factor receptor, transforming growth factor beta receptor, epidermal growth factor receptor and hedgehog pathway antagonists), mutated targets (B-Raf inhibitors), and downstream signalling targets (MEK inhibitors). While malignancies in patients often demonstrate an initial response to these drugs, cancer recurrence is frequently observed.
Dr Patel's research group over the last five years has defined cancer stem cells (CaSC) in the two commonest skin cancers, using internationally agreed assays. We have shown in high impact scientific publications that basal cell carcinoma (BCC) CaSC are resistant to both conventional chemotherapy and the recently approved growth factor inhibitor vismodegib. Microarray analysis of treated and untreated BCC CaSC reveals a novel role for the transforming growth factor beta pathway in mediating this resistance. In this proposal we plan to substantiate these findings experimentally and ask if blocking transforming growth factor beta signalling alone or in combination with vismodegib could result in CaSC killing.
The concept that cancer stem cells (CaSC) drive cancer relapse after growth factor targeted therapies was initially determined in chronic myeloid leukaemia (CML) treated with the BCR-ABL antagonist imatinib1. This new paradigm, in which CaSC drive relapse after growth factor targeted therapies is however best appreciated in cutaneous malignant melanoma treated with vemurafenib (see figure) and more recently basal cell carcinoma (BCC) treated with vismodegib. Although patients demonstrate an initial response, recurrence invariably occurs, typically with dramatic disease progression. Of note the relapse is associated with regrowth of the original tumour nodules, suggesting the presence of a residual and resistant tumour cell population that is able to repopulate the tumour; by definition CaSC. The key questions are why and how are CaSC resistant to growth factor inhibitors?
One quarter of all cancers exhibit activation of the hedgehog growth factor pathway, for which the archetypal cancer is BCC. A number of hedgehog pathway inhibitors are currently in clinical trials for a variety of malignancies, and this year the National Institute of Clinical Excellence (NICE) approved vismodegib for the treatment of inoperable and metastatic BCC. However, clinical studies already suggest that a BCC sub-population is resistant to vismodegib3-6. To date our group has defined BCC CaSC by expression of the cell surface protein CD200. Consistent with clinical experience we have experimentally shown that BCC CaSC are resistant both to conventional chemotherapy and vismodegib. Microarray analysis of vismodegib treated BCC CaSC suggest that they up-regulate the transforming growth factor-beta (TGF-beta) pathway, a hitherto poorly understood pathway in BCC, which is typically associated with epithelial-mesenchymal transition (increased invasiveness) in more aggressive cancers. Herein we hypothesise that the TGF-beta pathway is essential for BCC CaSC survival.
In this proposal we will define the TGF-beta pathway in human BCC, characterise the induction of TGF-beta signalling after vismodegib, and determine the effect of blocking TGF-beta signalling on BCC CaSC survival. The project, which will be undertaken in the new state-of the art Haydn Ellis research facility, will utilise a number of techniques including: cell culture, immune-labelling, cell and tissue imaging, RT-PCR, and siRNA technologies.
Start date: October 2014
Number of Studentships: 1
(1) Bhatia R, et al. Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood. 2003; 101: 4701–4707.
(2) Wagle N, et al. Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J Clin Oncol 2011; 29: 3085-96.
(3) Von Hoff DD, et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med 2009; 361: 1164–1172.
(4) Metcalfe C, de Sauvage FJ. Hedgehog fights back: Mechanisms of acquired resistance against Smoothened antagonists. Cancer Res 2011; 71: 5057–5061.
(5) Skvara H, et al. Topical treatment of Basal cell carcinomas in nevoid Basal cell carcinoma syndrome with a smoothened inhibitor. J Invest Dermatol 2011; 131: 1735–1744. (6) Sekulic A, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 2012; 366: 2171–2179.
This 3 year studentship is funded by Cancer Research Wales and will include a stipend of at least £14,000 p.a and tuition fees at Home/EU rate. Overseas students are welcome to apply but will need to provide their own funding to cover the difference between Home/EU and Overseas tuition fees.
Residency: This studentship is open to students of any nationality. Students classified as international for fee purposes have to self-fund the difference between home and international fees.
Academic criteria: Candidates should hold a First or Upper Second Class Honours BSc degree and/or a Masters degree, or equivalent degree in a science related subject.
How to Apply
To apply, complete the online application form on the School of Biosciences website. Please clearly indicate in your application that you wish to apply for this project.
The deadline for applications is 16 June 2014.
Cardiff University reserves the right to close applications early should sufficient applications be received.
For further information please contact the School of Biosciences on +44 (0)29 2087 5243 or at KhandavalliS@cardiff.ac.uk.