Advances made in recent years in identifying tyrosine kinases as signalling molecules governing proliferation and invasiveness have revealed the importance of their genetic alterations in the road to cancer. In particular, a little more than half of the known receptors tyrosine kinases have been repeatedly found either mutated or overexpressed in human malignancies, including sporadic cases. This has opened a whole new field of research aimed at developing new therapeutics by targeting tyrosine kinases. The success of Gleevec (an inhibitor for the Abl tyrosine kinase) in the treatment of Chronic Myeloid Leukemia has shown the potential of small molecule inhibitors as anticancer drugs. Furthermore, its rapid progress into clinical development has highlighted the importance of identifying the appropriate clinical setting for efficacy testing.
We have preliminary evidence that an ATP-analog, known as a Trk inhibitor, may also be active on Met-mediated tumours. Treatment of nude mice carrying xenotransplants of a gastric carcinoma line over-expressing Met caused complete regression of the tumours after four weeks.
We propose to further validate the anticancer potential of the drug in xenotransplants of other Met-positive tumour cell lines, and to ultimately test it in double transgenic mouse models for rhabdomyosarcoma and melanoma, two cancers for which there is a very strong rationale for causal involvement of the Met gene. The former is the most common solid tumour of childhood, and the latter is one of the fastest easing type of cancers in the world. Both tend to be particularly malignant and resistant to traditional therapy. The results of these pre-clinical tests may be critical in guiding the choice of patients for subsequent clinical trials.
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