| INVESTIGATION
OF THE MECHANISM OF SPHINGOSINE KINAS-1 INHIBITION BY
DOCETAXEL.
Dr Dmitry Pshezhetskiy Imperial College London, Prostate Cancer Laboratory |
 |
Prostate cancer is now the commonest cancer of men and the second most common cause of male cancer death. The management of prostate cancer is complex. Surgery or radiotherapy are used to treat early stage prostate cancer, and hormonal therapy is used to treat advanced disease. But up to 90% of patients with high grade localised prostate cancer and virtually all patients with advanced disease relapse. For these patients chemotherapy may be offered.
Docetaxel chemotherapy either in combination or as a single agent was shown to provide a survival advantage for patients. This advantage is however minor, and of a median period of less than 3 months. There is an urgent imperative to improve upon this survival benefit. We need to develop chemotherapy that provides a more significant advantage for our patients. It may be that we can improve survival by the addition of agents that sensitize prostate cancer cells to conventional chemotherapy and this is an approach that requires investigation. We have investigated a biochemical pathway whose modulation offers an opportunity for chemosensitisation. Our recent findings indicate a strong link between upregulation of the sphingosine kinase-1 (SK1) pathway and prostate cancer development in human patients. Moreover, in a recent publication we have identified SK1 as a molecular target for docetaxel treatment of hormono-refractory prostate cancer tumours.
Further investigation of the mechanisms by which SK1 pathway is involved in tumour progression and resistance to therapies might give an additional insight into its role in development of prostate cancer and provide grounds for evaluation of SK1 pathway as potential therapy target.
In our current research proposal we aim to identify the mechanisms by which docetaxel induces SK1 dowregulation and to study in detail how this process affects prostate cancer progression. We will then go on to investigate whether pharmacological inhibition of SK1 might serve as a chemo- and radio-sensitising tool in hormone-refractory prostate cancer. Our results might lead to further understanding of the mechanisms of docetaxel action on solid tumours. Additionally we will examine the possibility to bring further rational for the use of SK1 inhibitors as chemosensitizers.
Research summary, 25 March 2008.
Project 2007/07