Colorectal cancer is the third leading cause of cancer-related deaths in the western world. Approximately 20% of colorectal cancer patients present metastatic disease at diagnosis and approximately 35% of patients diagnosed at early stages will relapse after treatment.
Despite therapeutic advances, the prognosis of metastatic colorectal cancer patients remains poor due to intrinsic or acquired tumor drug resistance with a five-year survival rate lower than 20%. The main mechanisms of tumor drug resistance are represented by genetic and epigenetic alterations. This leads to tumor refractoriness during treatment or disease progression following response to first-line therapy. Strategies to combat chemorefractory tumors involve the development of selective inhibitors of drug-resistant phenotypes, the epigenetic resensitization of drug-resistant cancer cells and new cytotoxic drugs devoid of cross resistance with first-line cytotoxics. The use of drug combination regimens may also increase treatment efficacy, and the exploitation of specific phenomena such as oncogenic and nononcogenic addiction or synthetic lethality represents another potential approach in combating tumor drug resistance.
In a recent article we describe results of the most recent clinical trials based on such strategies in mCRC patients whose tumors progressed following first-line chemotherapy.
In our opinion, results from such trials as well as from the ongoing ones will add some important insights. The design and implementation of trials based on geno/pheno-stratification of mCRC patients while investigating targeted agents is of pivotal importance for the development of new precision medicines. This approach will enable a more rational application of fundamental biomolecular knowledge and more relevant advancements in clinical research and practice.
Article: Nobili S, Galletta A, Brugia M, Tassi R, Petreni P, Landini I, Mini E (2015). Emerging drugs in refractory colorectal cancer. Future Medicinal Chemistry, 7(12), 1491–1501.