Funded Research 2006

Importance of Interleukin-8 signalling as a mode of resistance of prostate cancer cells to Ionizing Radiation.
Dr David Waugh, Queen's University, Belfast

Prostate cancer is diagnosed in more than 30,000 men and is responsible for the deaths of more than 10,000 annually in the United Kingdom. Radiotherapy, alone or in combination with hormone ablation therapy, is a safe and effective treatment for the majority of patients with organ-confined prostate cancer. Unfortunately as many as 30% of patients treated with radiotherapy will eventually develop a recurrence of their cancer. Attempts to increase the effectiveness of radiotherapy are clinically important, since patients who relapse following treatment will will almost certainly go on to develop spread of their cancer to other parts of the body in particular the bones for which there is no curative therapy. One method of increasing the effectiveness of radiotherapy is to sensitise prostate cancer cells by using drugs such as platinum-based chemotherapy. These drugs can increase the amount of damage to the DNA of the cancer cells and make it more likely that radiotherapy (which also works by causing DNA damage) will result in the death (apoptosis) of the prostate cancer cells. Our pre-clinical study is designed to characterise additional strategies which may increase the sensitivity of prostate cancer cells to IR, by identifying and then attempting to interfere with a particular mechanism used by prostate tumours to resist the effects of radiation.

A reduced level of oxygen in tumours (hypoxia) is a well recognised cause of resistance to IR in prostate cancer as well as a cause of disease progression. This suggests that factors whose expression is increased during periods of oxygen deprivation may contribute to the resistance to therapy. In addition, ionizing radiation itself can have direct impact in regulating gene expression within prostate cancer cells, increasing the expression of proteins that may reduce the response rates to this treatment strategy. Our laboratory has observed that the expression of the pro-angiogenic chemokine, interleukin-8 (IL-8) is induced in prostate cancer cells in response to both hypoxia and upon exposure to IR. Of perhaps greater significance, is our observation that prosate cancer cells also increase the expression of the two receptors, CXCR1 and CXCR2 that mediate the biological response of IL-8, in response to both hypoxia dn ionizing radiation. Therefore, in addition to its established pro-angiogenic function upon endothelial cells, hypoxia and ionizing radiation potentiate IL-8 signaling in the cancer cells within the tumour microenvironment. We have subsequently shown that IL-8 signaling promotes the induction of genes that protent the cell from the effects of IR and hypoxia.

When this stress-induced IL-8 signaling is inhibited, the effectiveness of ionizing radiation on prostate cancer cells is increased while at the same time reducing the ability of cells to survice in a hypoxic environment.

Thanks to the PROSTATE CANCER RESEARCH FOUNDATION funding, we will determine the mechanism by which IL-8 signaling is potentiated by ionizing radiation and confirm its importance in modulating the response of cancer cells to ionizing radiation, using several complimentary approaches. The second aspect of work will explore how we can use platinum drugs and/or hormones in combination with novel anti-IL-8 signaling drugs to help sensitize prostate cancer cells to radiotherapy. If justified by the outcomes of our pre-clinical research, we intend to design a prospective clinical trial to establish whether IL-8 expression is predictive of response to radiotherapy and/or whether reducing IL-8 signaling might sensitize prostate cancer cells to radiotherapy.

 

Project commenced
September 2006

Length of project
3 years

Amount Supported
£81,000

 

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