The role of P21/Cdc42/Rac1-activated kinases (PAK) in prostate cancer.

Prostate cancer is the second leading cause of cancer death in men in the West. It is initially treatable with androgen deprivation therapy but eventually progresses to become insensitive to the treatment we have. The next stage is to have chemotherapy, which gives an average survival of between 10 and 20 months. We know that the main receptor responsible for prostate cancer growth (androgen receptor) has an effect on the different cell signaling pathways within the cell, particularly those involved in cell growth and cell movement. New links have shown one of the ways this relationship occurs is through energy regulating pathways. What we are aiming to do is to show a link between the energy regulating pathways and cell growth and cell movement. The aim is to concentrate on one of these mechanisms - the Rac1/PAK1 pathway - and determine its role in prostate cancer growth and metastasis. We know that more aggressive prostate cancers have higher levels of Rac1 and PAK1 but we do not yet know what their role is in the development of prostate cancer or its effect on cancer growth and spread. We aim to find out the mechanisms by which it works and the pathways that regulate it. This will initially be in the laboratory in cells but also on human tissue from specimens. The aim is to eventually discover new targets for the development of new medicines to help control prostate cancer.

To elicit new therapeutic interventions for prostate cancer, we must determine pathways involved in cancer initiation, growth and metastases. Cell signalling pathways are involved in all of these roles.

The Rho GTPases Cdc42 and Rac1, are molecular switches to a wide array of cellular functions. The main downstream effector for these are the P21-associated kinases (PAK), which have become of interest in cancer. These pathways are involved in a number of cellular processes including cytoskeletal dynamics and actin polymerization, growth factor and steroid hormone signalling, transcription, mitosis, apoptosis and facilitating the metastatic cascade.

There is evidence in a number of different cancer models, particularly breast, that the Rac1/PAK1 pathways help regulate tumourigenesis. In the prostate, Rac1 levels are elevated, particularly in castrate resistant disease, and higher expression correlates with poorer outcome. There is evidence implicating Rac1 as a key mediator for the interaction of prostate cancer cells with bone marrow endothelium during osseous invasion. The evidence for PAK1 expression in prostate cancer is limited but high levels of expression have been demonstrated to relate to Gleason score.
In vascular tissue, Rac1 is regulated by the CAMKK2/AMPK axis. This pathway acts as an intracellular metabolic master-switch. In our laboratory, we have established the regulation of CAMKK2 and AMPK through androgen receptor (AR) signalling in prostate cancer cells. This link is beginning to shed some light on the metabolic functions associated with the AR.

The aim of this project will be to investigate the role of Rac1/PAK1 signalling in the progression of prostate cancer, including castrate resistant cancer, with reference to the AR and metabolic signalling. It is hoped that the results from these studies will increase our knowledge of the processes involved in prostate cancer progression and metastasis and provide targets for drug intervention.

Ultimately we hope that this project will impact on patients with cancer. The pathway of interest is implicated in prostate cancer initiation, progression and metastases and possibly androgen independent prostate cancer growth. The significance of this is to patients whose advanced prostate cancers have escaped conventional chemotherapy. In these groups, we may be able to apply discoveries from our project to creating novel drug targets or using existing drugs in new applications to manipulate the pathways. The short term goal is to discover novel pathways suitable for drug modulation to achieve cancer control with existing drugs e.g. simvastatin, metformin. These two drugs act upstream on potential targets of our pathways of interest. The long term goal is to target key pathways with novel drug medications using data/information gleaned from our study. We anticipate that targeted combination therapy will be the outcome i.e. androgen blockade, chemotherapy +/- new agents with specific molecular targets e.g. Rac1 or PAK1. This is potentially life-prolonging therapy in those with castrate resistant prostate cancer.

The role for Rac1 or PAK1 as a prognostic or diagnostic marker of disease aggressiveness is interesting and if proven will be a very exciting tool in cancer diagnosis and may greatly impact patient care. If validated in humans, a very useful application would be to be able to risk stratify patients into high and low risk cancer groups on the basis of their biopsy expressing high or low levels of Rac1 or PAK1.

This project of research directly impacts those within my laboratory as well as the wider scientific community. Together with my supervisor and others in the laboratory, we will develop skills in experimental methodology and techniques. This will impact on future research as we will be equipped with the skills to further the findings in this project and other areas of research interest.

Having created a stable Rac/PAK1 overexpressing cell line, others in the laboratory will also benefit from the use of this in their own future work. With the results being presented and available to those within the local institutions such as the MRC-LMB building and the University, it will benefit them with ideas and information. The data will also be presented at national/international meetings both for urological research and cancer research, as well as being published in a journal for international distribution. This dissemination of results will benefit those interested in prostate cancer research. However, given the nature of the areas of interest, it should also be of interest to those researching androgen signaling, cell cycle and signaling and those with an interest in metabolism and cancer. The overall aim is to discover a unique druggable pathway in treating prostate cancer and to this end, it will also interest those doing clinical pharmacological research. There is also the potential for commercial impact if the local Cancer Research Technologies (CRT) feel a commercial product is viable.