In the early 1980s, it became apparent that the work of pioneers such as Robert Weinberg, Mariano Barbacid and many others in identifying cancer-causing genes in humans was opening the door to a new era in anticancer research. Motivated by this, and by dissatisfaction with the limited efficacy and tolerability of available anticancer modalities, a drug discovery programme was initiated with the aim of rationally developing targeted anticancer therapies. Here, we describe how this programme led to the discovery and continuing development of Glivec (Gleevec in the United States), the first selective tyrosine-kinase inhibitor to be approved for the treatment of a cancer.

Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug

Purpose Cabozantinib, a tyrosine kinase inhibitor (TKI) of hepatocyte growth factor receptor (MET), vascular endothelial growth factor receptor 2, and rearranged during transfection (RET), demonstrated clinical activity in patients with medullary thyroid cancer (MTC) in phase I. Patients and Methods We conducted a double-blind, phase III trial comparing cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomly assigned (2:1) to cabozantinib (140 mg per day) or placebo. The primary end point was progression-free survival (PFS). Additional outcome measures included tumor response rate, overall survival, and safety. Results The estimated median PFS was 11.2 months for cabozantinib versus 4.0 months for placebo (hazard ratio, 0.28; 95% CI, 0.19 to 0.40; P < .001). Prolonged PFS with cabozantinib was observed across all subgroups including by age, prior TKI treatment, and RET mutation status (hereditary or sporadic). Response rate was 28% for c...

/pdf/cabozantinib-in-progressive-medullary-thyroid-cancer-3taoee497y.pdf

Cabozantinib in Progressive Medullary Thyroid Cancer

Thyroid cancer is a common type of endocrine malignancy, and its incidence has been steadily increasing in many regions of the world. Initiation and progression of thyroid cancer involves multiple genetic and epigenetic alterations, of which mutations leading to the activation of the MAPK and PI3K-AKT signaling pathways are crucial. Common mutations found in thyroid cancer are point mutation of the BRAF and RAS genes as well as RET/PTC and PAX8/PPARγ chromosomal rearrangements. The mutational mechanisms seem to be linked to specific etiologic factors. Chromosomal rearrangements have a strong association with exposure to ionizing radiation and possibly with DNA fragility, whereas point mutations probably arise as a result of chemical mutagenesis. A potential role of dietary iodine excess in the generation of BRAF point mutations has also been proposed. Somatic mutations and other molecular alterations have been recognized as helpful diagnostic and prognostic markers for thyroid cancer and are beginning to be introduced into clinical practice, to offer a valuable tool for the management of patients with thyroid nodules.

Molecular genetics and diagnosis of thyroid cancer

This review discusses the development and uses of imatinib mesylate, a protein tyrosine kinase inhibitor useful in the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors that was recently approved by the Food and Drug Administration Imatinib targets platelet-derived growth factor receptor, inhibits the fusion product of the Philadelphia chromosome, and targets c-kit, a protein tyrosine kinase The drug may also be effective in the treatment of other tumors that express platelet-derived growth factor receptor or c-kit

Imatinib Mesylate — A New Oral Targeted Therapy

Transcription factors of the NF-kappaB family regulate hundreds of genes in the context of multiple important physiological and pathological processes. NF-kappaB activation depends on phosphorylation-induced proteolysis of inhibitory IkappaB molecules and NF-kappaB precursors by the ubiquitin-proteasome system. Most of the diverse signaling pathways that activate NF-kappaB converge on IkappaB kinases (IKK), which are essential for signal transmission. Many important details of the composition, regulation and biological function of IKK have been revealed in the last years. This review summarizes current aspects of structure and function of the regular stoichiometric components, the regulatory transient protein interactions of IKK and the mechanisms that contribute to its activation, deactivation and homeostasis. Both phosphorylation and ubiquitinatin (destructive as well as non-destructive) are crucial post-translational events in these processes. In addition to controlling induced IkappaB degradation in the cytoplasm and processing of the NF-kappaB precursor p100, nuclear IKK components have been found to act directly at the chromatin level of induced genes and to mediate responses to DNA damage. Finally, IKK is engaged in cross talk with other pathways and confers functions independently of NF-kappaB.

IkappaB kinase complexes: gateways to NF-kappaB activation and transcription.

TRK-fused gene (TFG) was first identified as a partner of NTRK1 in generating the thyroid TRK-T3 oncogene, and is also involved in oncogenic rearrangements with ALK in anaplastic lymphoma and NOR1 in mixoid chondrosarcoma. The TFG physiological role is still unknown, but the presence of a number of motifs involved in protein interactions suggests that it may function by associating with other proteins. We have recently demonstrated that TFG associates and regulates the activity of the tyrosine phosphatase SHP-1. In this study by yeast two-hybrid screening we identified NEMO and TANK, two proteins modulating the NF-kappaB pathway, as novel TFG-interacting proteins. These interactions were further characterized in vitro and in vivo. We provide evidence that TFG and NEMO may be part of the same high molecular weight complex. TFG enhances the effect of TNF-alpha, TANK, TNF receptor-associated factor (TRAF)2, and TRAF6 in inducing NF-kappaB activity. We suggest that TFG is a novel member of the NF-kappaB pathway.

The TFG protein, involved in oncogenic rearrangements, interacts with TANK and NEMO, two proteins involved in the NF‐κB pathway

The TRK-T3 oncoprotein, isolated from a human papillary thyroid tumor, arises from the fusion between the N-terminal domain of the TFG gene and the tyrosine kinase domain of the NTRK1 receptor. The 68 kDa TRK-T3 oncoprotein displays a constitutive tyrosine kinase activity resulting in its capability to transform NIH3T3 cells. The TFG portion of TRK-T3 contains a coiled-coil domain, which mediates protein oligomerization essential for the oncogene constitutive activation, and several consensus sites for protein interaction. In this study, we investigate the role of TFG sequences outside the coiled-coil domain on TRK-T3 activation, We constructed four mutants carrying different deletions of TFG sequences and expressed them in mammalian cells. By performing biochemical and biological assays we demonstrated that all the deleted regions are required for TRK-T3 activation, as they are involved in different mechanisms such as protein processing, formation of stable and/or functional complexes, and possible interaction with other proteins. By constructing site-specific mutants, we demonstrated a crucial role for a PB1 domain and a considerable contribution of an SH2-binding motif in TRK-T3 oncogenic activation. This work establishes an important role for TFG sequences outside the coiled-coil domain in the activation of the thyroid TRK-T3 oncogene.

Role of TFG sequences outside the coiled-coil domain in TRK-T3 oncogenic activation.

The thyroid TRK-T3 oncogene, produced by a chromosomal translocation, is a chimeric, constitutively activated version of the NTRK1/NGF receptor and it is able to transform NIH3T3 cells and differentiate PC12 cells. TRK-T3 oncoprotein triggers multiple signal transduction pathways. Among others, TRK-T3 binds and phosphorylates the Shc and SNT1/FRS2 adaptor proteins both involved in coupling the receptor tyrosine kinase to the mitogen-activated protein kinase pathway by recruiting Grb2/SOS. We were interested in defining the role of Shc in the oncogenesis by TRK-T3. The mutation of TRK-T3 tyrosine 291, docking site for both Shc and FRS2, abrogates the oncogene biological activity. To directly explore the role of Shc we used the ShcY317F mutant, which carries the mutation of a tyrosine residue involved in Grb2 recruitment. We demonstrated that the ShcY317F mutant exerts an inhibitory effect on TRK-T3 transforming activity. Such effect can be modulated by the amount of ShcY317F protein and affects the viability of cells expressing TRK-T3 by means of a mechanism involving apoptosis. Our results indicate a definitive role of the adaptor protein Shc in TRK-T3 transforming activity.

/pdf/biological-activity-of-the-thyroid-trk-t3-oncogene-requires-16146vpz19.pdf

Biological activity of the thyroid TRK-T3 oncogene requires signalling through Shc

The NTRK1 gene encodes the high affinity receptor for Nerve Growth Factor, and its action regulates neural development and differentiation. Deregulation of NTRK1 activity is associated with several human disorders. Loss of function mutations cause the genetic disease Congenital Insensitivity to Pain with Anhidrosis (CIPA). Constitutive activation of NTRK1 has been detected in several tumor types. An autocrine loop involving NTRK1 and NGF is responsible for tumor progression in prostate carcinoma and in breast cancer. Somatic rearrangements of NTRK1, producing chimeric oncogenes with constitutive tyrosine kinase activity, have been detected in a consistent fraction of papillary thyroid tumors. The topic of this review is the thyroid TRK oncogenes; the modalities of activation, the mechanism of action, and the contribution of activating sequences will be discussed.

TRK oncogenes in papillary thyroid carcinoma.

Analysis of SHP-1-mediated down-regulation of the TRK-T3 oncoprotein identifies Trk-fused gene (TFG) as a novel SHP-1-interacting protein.

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