Title: Personalized prevention of colorectal neoplasia by use of genetic variability for the prediction of efficacy and toxicity of treatment with COX-2 inhibitors and aspirin.

Project Coordinator:
Nadir ARBER (Israel) Tel Aviv Sourasky Medical Center, Tel Aviv

Project Partners:
Robert BENAMOUZIG (France) Hopital Avicenne, Bobigny
Cristiano CROSTA (Italy) European Institute of Oncology, Milan
Angel LANAS (Spain), Hospital Clínico Universitario Lozano Blesa, Zaragoza
Jaroslav REGULA (Poland) Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw
Dominique SCHERER (Germany) German Cancer Research Center, Heidelberg

Project Abstract:
Colorectal cancer (CRC) is a major health concern worldwide. Its heterogeneous nature requires personalized prevention strategies to reduce the public health burden of the disease. The most promising agents for CRC chemoprevention are NSAIDs (e.g. aspirin, COX-2 inhibitors), which were associated with a significant reduction of adenoma recurrence in several trials (PreSAP, APACC, APPROVe), however, accompanied by increased risk of gastrointestinal and cardiovascular toxicities. We and others have shown that genetic variants can modify the risk of CRC in interacting with the mechanism of action of NSAIDs. In addition, our preliminary study suggests that certain variants interact with and modify the efficacy and symptoms/toxicity of NSAIDs in colorectal adenoma patients. The proposed study is a translational pharmacogenetic study ancillary to three multicenter trials on the secondary prevention of colorectal adenomas aimed to; establish the use of genetic variability as biomarkers for colorectal adenoma recurrence, and COX-2 inhibitor-related treatment efficacy, and symptoms/toxicity within the PreSAP; validate the identified biomarkers for the use of other COX inhibitors in samples from APPROVe (rofecoxib), as well as in samples from the APACC trial (aspirin), thus identifying similarities and differences in response to another COX-2 inhibitor. This project is a unique approach for developing personalized chemoprevention strategies by use of genetic fingerprints that can maximize the benefit/risk ratio of COX-2 inhibitors and aspirin in individuals at high risk of CRC.

(Project funded under JTC 2012)