Dr Ultan McDermott

Title: Thymidylate synthase, p53 and apoptotic genes as markers of response in gastrointestinal cancer

Project Start Date: August 2002

Completion Date: August 2005

Summary:

Colon cancer is the second most common cause of cancer death in Europe. Despite recent advances in the development of new chemotherapeutic agents the management of colon cancer continues to be sub-optimal in two main areas: (1) the prediction of those patients most likely to benefit from chemotherapy and, (2) the determination of which chemotherapy drugs to use. The use of chemotherapy over the last thirty years has produced major improvements in overall outcome for colon cancer patients but the development of resistance to chemotherapy drugs remains one of the biggest obstacles in the treatment of this group of patients.

Recent results from our laboratory have caused us to focus on a protein (receptor) that lies on the surface of the cell and which normally enables the body’s immune system to attack and remove any abnormal cells before they can become malignant. Many cancer cells appear to have developed ways to prevent this cell surface receptor from functioning normally. Identifying the ways cancer cells can block this signalling may enable us to develop therapies to target (or ‘unblock’) these pathways and restore normal function. This in turn would render the cancer cells more vulnerable to the chemotherapy drugs used in clinical practice as well as to the body’s own immune system.

My research to date has shown that many of the chemotherapy drugs used in the treatment of colon cancer increase the expression of the Fas death receptor in colon cancer cell lines. If we combine these drugs with an antibody which activates the receptor we increase significantly the number of cancer cells killed by the drugs. In addition, in cells which harbour a mutation in an important gene called p53, this increased expression of Fas is not seen with most of the drugs. This finding is important given that almost half of the patients who develop a colon cancer will have a mutation in this gene. What we did find, however, is that one of the chemotherapy drugs called CPT-11 was still able to increase expression of this receptor even in these p53 mutant cells, and that genes outside of p53 may be involved.

The ability of many drugs to increase expression of the Fas death receptor in colon cancer cell lines raises the possibility of using an antibody similar to the one used in our lab to activate the receptor and cause increased cancer cell death when used in conjunction with conventional chemotherapy agents. Secondly, the ability of one drug (CPT-11) to induce the receptor in p53 mutant cells may mean that in these patients it should be used in preference to the other chemotherapy drugs to enable the antibody to have the desired effect. These approaches have the potential to dramatically increase the therapeutic effect of current treatment approaches to colon cancer.

The ability of antibodies which bind to the Fas receptor in colon cancer cells to enhance cancer cell kill raises the possibility of using these antibodies in clinical practice to improve patient care. Initial studies of such antibodies were hampered by excess liver toxicity with the first antibody tested, but studies are ongoing to develop safer alternatives. In addition, the data presented in this research indicate that certain chemotherapy agents are more efficacious in activating the Fas death receptor and priming the cells to respond to the antibody in p53 mutant cells. As p53 mutations are found in 50-60% of colon cancers, chemotherapy agents such as CPT-11 should be used in combination with anti-Fas antibodies.

It is important to understand why a chemotherapy agent such as CPT-11 is able to increase expression of the Fas death receptor in p53 mutant cells, whereas others such as 5-FU and oxaliplatin are not. The ability to take a feature of tumours such as p53 status and tailor treatment to it has the potential to increase the response to anti-cancer therapies.