Study identifies biomarkers that predict patients’ response to certain colon cancer drugs

May 21, 2012 by Journal of Molecular Biomarkers and Diagnosis

The Stem Cells and Cancer Research Group headed by Dr H-ctor G. Palmer at the Vall d’Hebr-n Institute of Oncology (VHIO) has identified the molecular mechanisms that determine patients’ response to certain drugs used in clinical trials for colon cancer treatment. The study led by VHIO also benefited from the collaboration with Professor Alberto Mu-oz-s laboratory at the Instituto de Investigaciones Biomedicas Alberto Sols, Consejo Superior de Investigaciones Cient-ficas (IIB-CSIC-Madrid). Published today in Nature Medicine, this work identifies biomarkers that predict response to treatment and proposes therapeutic solutions for patients who do not respond well. These advances will guide better selection of treatments and avoid the risk of administering ineffective drugs.

Colon cancer is a disease caused by a malignant tumour in the large intestine. When detected early the tumor is removed through surgery and patients are treated with adjuvant chemotherapy, eliminating the disease in the majority of cases. However, in advanced stages, colon tumours are resistant to a broad spectrum of anti-tumour drugs and cancerous cells escape treatment and disseminate around the body, giving rise to metastasis. Currently there are no effective treatments to halt the progression of colon cancer in these later stages and most patients die as a result of disease progression.

Over recent years new drugs have been designed to target and block the activity of certain molecules responsible for promoting tumor growth and metastasis. Some of these, which are currently in clinical trials, are showing promising results in certain patients, while others show no improvement at all. This study headed by the VHIO examines the differential response to treatment and was supported by the Olga Torres Foundation (FOT), the Scientific Foundation of the Spanish Association Against Cancer (AECC), and the Carlos III Institute of Health (ISCIII).

New clinical horizons

Dr H-ctor G. Palmer-s team has described for the first time the molecular mechanisms through which the interaction between the oncogenic pathways of Wnt/beta-catenin and RAS/PI3K/AKT determines the response to treatments with pharmacological PI3K or AKT inhibitors. Although both pathways are genetically altered in colon cancer, it is the over-accumulation of beta-catenin in the nucleus of cancer cells that makes them resistant to cell death induced by these anti-tumoral drugs.

Activation of the PI3K/AKT pathway retains the FOXO3a protein outside the cell nucleus, inhibiting its ability to act as a tumour suppressor that induces cell death. Therefore, “Targeting PI3K or AKT activity with these novel inhibitors allows relocation of FOXO3a in the nucleus promoting cell death. These drugs are being tested in clinical trials worldwide providing promising initial results in certain tumour types”, explains H-ctor G. Palmer, Head of VHIO-s Stem Cells and Cancer Group.