Relevance of Interleukin-8 and c-FLIP in promoting resistance to anti-androgen therapy and as biomarkers of elevated risk of androgen-independence in prostate cancer

Dr David Waugh, Dr Jo O'Sullivan & Dr Daniel Longley, Queen's University, Belfast

The growth of prostate cancer (CaP) tumours is stimulated by the male hormone, testosterone.  Anti-testosterone treatments are therefore used commonly in the management of prostate cancer.  While this is frequently effective, many patients eventually develop resistance to this type of treatment.  Unfortunately, we are unable to identify all those patients at elevated risk of developing androgen-independent CaP.  Therefore, ways of identifying this risk would have significant clinical benefit, enabling clinicians to use alternative therapies earlier in the treatment of these patients.  We have shown that CaP cells have increased levels of a protein called interleukin-8 (IL-8) which promotes growth of CaP cells despite anti-testosterone therapy.  Blocking IL-8 signalling increases the sensitivity of CaP cells to anti-testosterone therapy.  IL-8 induced AR activity increases the level of a protein termed c-FLIP that enables CaP cells to acquire resistance to therapeutic agents.  We aim to determine whether we can sensitize CaP cells to Casodex, a clinically used AR-antagonist, by suppressing the expression of c-FLIP in CaP cells.  Secondly, we will characterise the expression of IL-8 and c-FLIP in patients with CaP prior to, during and following anti-testosterone therapy.  The expression of these proteins will be correlated to the patient's clinical response, determining whether elevated expression of IL-8 and c-FLIP may signify those patients who respond poorly and who will ultimately develop recurrence of their cancer

Project commenced

January 2009

Length of project

3 years

Amount supported

£58,784