Receptors for growth factors are membrane proteins that are activated by binding to the ligand. Ligand activation causes swichting on receptor enzimatic function, consisting in transfer of a phosphate group from ATP to specific tyrosine residues contained either on the receptor itself or on external protein substrates. The phosphorylation event induces a signal cascade that leads to cellular proliferation and/or survival. Therefore any perturbation of such a system can lead to neoplastic transformation. Many receptor for growth factors, indeed, are mutated in human tumors.
One of them is Ret, receptor of neurotrophins belonging to the Glial Derived Neurotrophic Factor (GDNF). Germline point mutations of RET cause the inherited multineoplastic disorder Multiple Endocrine Neoplasia type 2 syndrome (MEN2). MEN2 patients are affected by medullary thyroid carcinoma (MTC), derived from C cells of the thyroid. MTC can be associated to adrenal medulla pheocromocytoma, parathyroid adenoma and neuroma and ganglioneuroma of the gut. MEN2 RET mutations are localized in the ligand binding site or in the ATP and protein substrate binding site. RET is activated also in 30% of papillary thyroid carcinoma (PTC), originating from follicular cells. In this case oncogenic activation is caused by chromosomal rearrangements fusing the tyrosine kinase domain of Ret to heterologous sequences, inducing constitutive activation of the enzyme. PTC are often associate to exposure to ionizing radiations, causing DNA breaks and abnormal chromosomal fusions. Indeed, RET rearrangements are particolarly frequent in PTC arising after Chernobyl nuclear disaster.
A new strategy for fighting cancer is inhibition of mutated growth factor receptors by small molecular weight inhibitors, able to block kinase function by competing with ATP. In the project "Molecular mechanisms of neoplastic transformation", point 6a, number 030.001, we have identified three different RET inhibitors, the pyrazolopyrimidine PP1 and PP2 and the anilinoquinazoline ZD6474 (Astra Zeneca). The three compounds can block both RET-MEN2 and RET-PTC enzimatic activity. More over they are able to inhibit Ret driven neoplastic transformation both in cultured cells and in mice xenografted with human tumors carrying RET activation. Therefore these molecules represent a promising tool for thyroid medullary and papillary carcinoma sustained by RET mutations. It is important to say that MTC are generally not sensitive to classical chemotherapy and the only effective treatment is represented by surgery.
These research has been founded by Associazione Italiana Ricerca contro il Cancro, by Ministero della Sanita', by Ministero dell'Universita' e della Ricerca and by Consiglio Nazionale delle Ricerche.
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