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The anoikis suppressor TrKB as a target for novel anti-cancer agents

Final Report Summary - TRKCANCER (The anoikis suppressor TrKB as a target for novel anti-cancer agents)

The failure of anti-cancer therapies generally results from locally intractable invasive growth or from the presence of metastases refractory to treatment with curative intent. A novel therapeutic strategy is to develop new anti-cancer drugs specifically targeting the invasive or metastatic phenotype of tumour cells. The TRKCANCER project proposed to validate at the preclinical level a strategy that targets the critical mechanism allowing apoptosis evasion and survival of invasive or metastatic tumour cells. Anoikis is a process by which a cell detached from its resident tissue undergoes apoptosis as a result of loss of normal cell / matrix interactions. Loss of anoikis allows survival of cancer cells in abnormal microenvironments, such as tissue compartments invaded by the primary tumour, and the intravascular compartment during the metastatic process.

Participant 2 has recently discovered that the BDNF receptor TrkB is a potent suppressor of anoikis and is responsible for apoptosis evasion that occurs in aggressive human tumours overexpressing TrkB (Douma, Nature, 2004). The aim of the project was to validate TrkB as a target for new anticancer drugs, aiming to restore anoikis and thereby destroy the invasive and metastatic cancer cells. This validation included the identification TrkB-expressing tumour cell lines amongst a collection of resected human cancers. Then, abrogation of TrkB mediated signalling was achieved by either selective TrkB mRNA-targeting small interfering RNAs (siRNAs or shRNAs) delivered by viral vectors, or by novel and potent small molecule inhibitors that were designed and synthesised.

The efficacy of these tools were assessed by using anoikis-sensitive cell models and xenograft mouse models, particularly orthotopic metastasis models derived from human tumours. The mechanisms of TrkB-dependent anoikis suppression were also investigated in order to identify additional markers for invasive and metastatic capability and novel drug targets.

At the end of the contract, TrkB was not validated as a target for anti-cancer drugs, but encouraging results obtained yet and critical experiments still on-going. Three potent and selective TrkB inhibitors were selected for in vivo evaluation of antimetastatic properties. New mouse models for metastasis were in use and several alternative models were identified. New potential biomarkers for metastasis were identified as critical factors of TrkB pathway.

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