ABSTRACT
ABSTRACT: One of the most exciting developments in cancer research in recent years has been the clinical validation of molecular targeted therapies (MTTs) that inhibit the action of pathogenic tyrosine kinases, and in this context, medullary thyroid carcinoma (MTC) represents a promising model. In fact, it is well known that in MTC, the activated RET (rearranged during transfection) proto-oncogene product, the RET receptor tyrosine kinase, and its signal transduction pathways lead to subsequent neoplastic transformation. These mechanisms are highly attractive targets for selective cancer therapy. Several strategies aimed to block the activation and signaling of RET have been preclinically tested. They include the interference with formation of ligand-receptor complexes, dimerization, autophosphorylation, recruitment of adaptor proteins to various docking sites, and initiation of signal transduction cascades. Although almost all steps may be inhibited by relatively speciˆc agents, the most advanced results have been obtained by competitive inhibition of RET-TK activity by tyrosine kinases inhibitors (TKIs). A variety of novel approaches are currently being assessed in clinical trials. However, although the inhibition of the RET pathway is actually one of
21.1 Introduction .......................................................................................................................... 352 21.2 Tyrosine Kinases as Therapeutic Targets ............................................................................. 352
21.2.1 RET Receptor Tyrosine Kinase ................................................................................ 352 21.2.2 Targeting RET with TKIs: Clinical Trials ............................................................... 354 21.2.3 Other Strategies to Inhibit RET ................................................................................ 357
21.3 Targeting Other Kinases ....................................................................................................... 357 21.3.1 RAS-RAF-MAPK-ERK Pathway ............................................................................ 358 21.3.2 PI3K-Akt Pathway .................................................................................................... 358 21.3.3 GSK-3 as a Potential Target for MTC Growth Regulation ....................................... 358 21.3.4 Nerve Growth Factor Receptor Pathway .................................................................. 358 21.3.5 Insulin-Like Growth Factor Receptor Pathway ........................................................ 358 21.3.6 Fibroblast Growth Factor Receptor Pathway ............................................................ 359
21.4 Angiogenesis as a Therapeutic Target .................................................................................. 359 21.5 Other Targeted Approaches ..................................................................................................360
