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A key role for FKBPL in the regulation of cancer stem cell signalling and the microenvironment; therapeutic implications for tumour growth and metastasis

  • Full or part time
    Prof T Robson
    Prof D O'Connor
  • Application Deadline
    Monday, December 02, 2019
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

About This PhD Project

Project Description

Cancer stem cells (CSCs) are a special type of cell found within tumours that are able to undergo unlimited self-renewal and are highly resistant to therapy. Indeed, these cells are left behind and go on to divide rapidly, leading to tumour regrowth. Even more worrying, this population of cells have special features allowing them to move through the body, invading vital organs; a process known as metastasis.

We have identified a novel protein, called FKBPL, that occurs naturally in the body and which inhibits tumour blood vessel development, thereby stopping tumour growth. A therapeutic drug derived from the protein and designed to harness its therapeutic effects, has successfully completed phase I cancer clinical trials and was recently granted Orphan Drug status in ovarian cancer by the FDA. However, we have acquired data which suggests that this protein also targets breast and ovarian CSCs by transforming them into a more ‘normal’ cancer cell, which can be easily killed by chemotherapy. This project will assess the impact of FKBPL on other cells within the ovarian tumour microenvironment that are known to support the growth and survival of CSCs cells in the primary tumour and at distant sites.

We will evaluate exactly how FKBPL controls these cells and the implications on the ability of CSCs to become metastatic. Understanding
how this protein works will allow us to design future clinical trials that are more likely to demonstrate better response rates in cancer patients.

References

• Valentine A, O’Rourke M, Yakkundi A, Worthington J, Hookham M, Bicknell R, McCarthy H, McClelland K, McCallum L, Dyer H, McKeen
H, Waugh D, Roberts J, McGregor J, Cotton G, James I, Harrison T, Hirst D, Robson T FKBPL and peptide derivatives: novel biological
agents that inhibit angiogenesis by a CD44-dependent mechanism. Clin Cancer Res. 2011 Mar 1;17(5):1044-56.
• McClements L, Yakkundi A, Papaspyropoulos A, Harrison H, Ablett MP, Jithesh PV, McKeen HD, Bennett R, Donley C, Kissenpfennig A,
McIntosh S, McCarthy HO, O’Neill E, Clarke RB, Robson T. Targeting treatment resistant breast cancer stem cells with FKBPL and its
peptide derivative, AD-01, via the CD44 pathway. Clin Cancer Res. 2013 Jul 15;19(14):3881-93.
• Annett S, Robson T. Targeting cancer stem cells in the clinic: Current status and perspectives. Pharmacol Ther. 2018 Jul;187:13-30.

Related Subjects



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