Colorectal cancer, the fourth leading cause of cancer deaths worldwide, is currently treated with chemotherapy combining a number of available medications. Despite improving life expectancy, patients often experience side effects and eventual resistance to the therapy. Newer, targeted biological therapeutics are also entering the clinic, increasing the range of combinational treatments possible. However, this also increases the difficulty in tailoring the proper therapy to the patient.

“The problem with design of combination therapy is the immense number of possible combinations. Another problem is that combination therapy is often based on previous success of the monotherapies in the clinic,” the authors said. “We have used statistical analysis and experimental testing to identify a four-drug combination therapy using exclusively biological-targeted compounds. This combination outperforms chemotherapy in preclinical models of colorectal cancer.”

Combining the power of models and experiments
In order to address the challenge of designing an effective anti‐cancer therapy containing multiple drugs, the researchers developed a new ‘therapeutically guided multidrug optimization’ (TGMO) technology, composed of both in silico modelling and experimental testing.

Amsterdam UMC colleagues prof. Arjan Griffioen, dr. Judy van Beijnum, prof. Connie Jimenez and former Amsterdam UMC prof. Patrycja Nowak-Sliwinska, in collaboration with a team from the Pharmaceutical Sciences Section of UNIGE and the University Hospitals of Geneva (HUG), published the results of their study in Molecular Oncology

Using TGMO, the researchers considered 11 drugs in 155 combinations, and identified an optimal low-dose synergistic combination of targeted drugs that outperformed standard chemotherapy combinations in human colorectal cancer cell lines and a murine colorectal cancer model. By comparing cancerous and healthy cells lines from the same patient, they were able maximize the therapeutic selectivity through multitarget inhibition, with results superior to that of standard treatment. They did not observe signs of drug-induced resistance, and the low-dose approach may limit side effects in clinical application. Their results also showed that the optimized combination was phenotype specific – it did not transfer to different colorectal cancer cell lines – emphasizing the importance of individualized drug combinations for patients. The authors have applied for patents based on the new methodology and plans for rapid clinical implementation.

Press release by the University Hospitals of Geneva in French: