Mechanism of action of statins in colorectal cancer

Jacobs, R.J. (2013)

Doctoral Thesis

The focus of our research and this thesis was to investigate how statins are able to influence colorectal cancer formation and whether they might be used as a chemopreventive or adjuvant therapeutic agent in colorectal cancer. As we have shown, statins are able to influence colorectal cancer cells at different levels from the level of BMP receptor expression and receptor cycling, effects on the entire kinome in cancer cells, to epigenetic changes via its ability to alter gene promoter methylation. Our results suggest that statins could provide an interesting and favorable option for use in a chemopreventive or adjuvant setting. There are however aspects which have to be assessed before a drug is used for chemoprevention. The risk/benefit ratio should be assessed carefully, especially when administered to healthy individuals. Ideally, a chemopreventive agent should fulfill certain criteria. Most importantly, the drug must be effective and exhibit minimal side-effects. The safety profile of a drug and efficacy varies significantly between patients and is dependent on disease severity. Therefore, it is of great importance to critically assess the possible benefits of chemoprevention in comparison to the risk and inconvenience that could come with it. In the general population the lifetime risk of CRC is 5 % and the number needed to treat to prevent one CRC death will be very high. In patients at average risk, compliance in this asymptomatic cohort outside a study is likely to be low. The balance of risk versus benefit is more in favor of its use in high risk groups such as individuals especially susceptible to colorectal cancer because of environmental risk factors (diet high in animal protein and fat), patients with inflammatory bowel disease (IBD) and those with a hereditary predisposition to CRC. These include patients with Familial Adenomatous Polyposis (FAP), Lynch Syndrome, Hereditary Non Polyposis Colon Carcinoma (HNPCC) and patients with a previous history of colorectal or adenomatous polyps. However, effective chemoprevention within one high risk group does not mean that the same chemoprevention is suitable for all groups. This stems from and also illustrates the fact that CRC is not one disease but a heterogeneous group of diseases with different underlying molecular mechanisms. Statins have an excellent safety profile, have been use for decades and have a beneficial effect on cardiovascular disease risk even in healthy individuals. Next to this we have shown that the use of statins has strong protective effect on the development of colorectal cancer expressing SMAD4 and does not increase the risk of developing CRC in SMAD4 negative tumors. Taken together our results suggest that statins could present a very interesting and favorable agent for use in a chemopreventive or adjuvant setting in CRC.

• Influence of statin use
• Colorectal cancer
• Chemoprevention
• Mechanism of action

• All authors: Jacobs, R.J.
• Supervisor: Hommes, D.W.
• Co-supervisor: Hardwick, J.C.H.; Kodach, L.L.
• Qualification: Doctor (dr.)
• Awarding Institution: Leiden University Medical Center (LUMC), Leiden University
• Date: 2013-10-10