Community Research and Development Information Service - CORDIS

FP6

ONCODEATH — Result In Brief

Project ID: 37278
Funded under: FP6-LIFESCIHEALTH
Country: Greece

Using TRAIL for cancer therapy

European scientists joined forces against cancer by delineating the TNF-related apoptosis-inducing ligand (TRAIL) apoptotic pathway and its potential use for cancer therapy.
Using TRAIL for cancer therapy
Traditional cancer treatments such as chemotherapy or radiotherapy suffer from cross-reactivity with normal cells. Innovations in the field of genetics are contributing to the design of new tailor-made drugs targeted to specific molecules of the cancer to be treated. Such approaches offer a more personalised treatment that is based on the molecular profile of the patient’s cancer.

TRAIL is currently a promising specific anti-cancer agent as it works in many tumours and has no effect on normal cells. It works by binding to specific death receptors (DRs) and triggering an intracellular cascade of events that lead to cell death.

Elucidation of the mechanisms that confer sensitivity or resistance to TRAIL-mediated apoptosis was the key objective of the EU project ‘Sensitisation and resistant determinants of cancer cells to death receptor-related therapies’ (ONCODEATH). More specifically, project partners focused on various oncogenes and their impact on TRAIL-induced cell death.

A series of tools for oncogene overexpression or silencing were developed to study oncogene pathway interaction with TRAIL in colon cancer. The ultimate goal was to use these pathways to activate TRAIL as a therapy against cancer.

Alternatively, TRAIL was proposed as a combination therapy with inhibitors of other key cancer pathways. Such inhibitors were generated and additional molecules identified that cooperate with TRAIL to induce cell death. An important ONCODEATH project finding was the simultaneous combinatorial treatment of choline or BRAF kinase inhibitors with TRAIL as a synergistic strategy against colon cancer. Combination of TRAIL with BRAF and PI3K inhibitors appeared as the most efficient combination towards colon cancer cell death.

Furthermore, the resistance to TRAIL was overcome in small cell lung carcinoma (SCLC) cells by rational combinations of TRAIL with epigenetic inhibitors of DNA Methyltransferases and Histone Deacetylases.

The ONCODEATH project has demonstrated how specific signalling pathways could be exploited for the generation of anti-cancer strategies. Such tumour-specific drugs are believed to have high therapeutic efficacy, lowering the treatment cost at the same time.

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