TrkB and NB

Activation of TrkB by its ligand BDNF has been shown to promote survival, alter sensitivity to chemotherapeutic drugs, and stimulate invasiveness - all properties of highly malignant tumors cells (Matsumoto et al. 1995) (see Chap. 5). An interesting aspect of the clinical behavior of poor prognosis NBs is that even though they are initially sensitive to chemotherapeutic agents, they often ultimately become resistant. The basis of this chemoresistance is probably multi-factorial being influenced by traditional chemoresistance factors such as the level of expression of drug efflux pumps such as MRP (Norris et al. 1996) and mutations in TP53 (Keshelava et al. 2001; Tweddle et al. 2001). In addition, the level of expression of BDNF and its receptor TrkB may also contribute to the escape of NB cells from the effects of cytotoxic chemotherapy. Drug-resistant NB cell lines have increased levels of expression of BDNF and the levels of BDNF increase as the cells become progressively resistant to higher concentrations of cytotoxic drugs (Scala et al. 1996). Additionally, both the concentration of BDNF and the level of expression of TrkB have been shown to diminish the sensitivity of cells to drugs typically used in the therapy of NB (Jaboin et al. 2002). Recent studies have identified two targets of the TrkB pathway amenable to drug development. A drug targeting Trk tyrosine kinases (CEP-701) is in clinical trials and has shown preclinical efficacy against NB mouse xenografts (Evans et al. 1999). Furthermore, a number of compounds targeting the PI-3-kinase pathway and its downstream targets are in pre-clinical development. Such agents may enhance the toxicity of chemotherapeutic agents against aggressive NB.

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