Receptor tyrosine kinases malignancy

Receptor Tyrosine Kinases and Their Role in Malignancy Targeting the Epidermal Growth Factor Receptor Family Clinical Trials with Anti-HER-2 Strategies Clinical Trials Targeting the EGFR (HER-1)... 

RECEPTOR TYROSINE KINASES AND THEIR ROLE IN MALIGNANCY... 

Rosen L, Hannah A, Rosen P, et al. Phase I dose-escalating trial of oral SU006668, a novel multiple receptor tyrosine kinase inhibitor in patients with selected advanced malignancies. Proc Am Soc Clin Oncol 2000 19 182 (abst). 

Reardon DA et al (2009) Phase I pharmacokinetic study of the vascular endothelial growth factor receptor tyrosine kinase inhibitor vatalanib (PTK787) plus imatinib and hydroxyurea for malignant glioma. Cancer 115 2188-2198... 

In summary, sunitinib maleate (1) is a multitargeted receptor tyrosine kinase inhibitor with potent anti-angiogenic and antitumor activity. It is approved for the treatment of advanced renal cell carcinoma and gastrointestinal stromal tumors, and is currently undergoing clinical trials for a number of additional malignancies. The discovery synthesis of 1 along with its process development approaches were described in this chapter. 

Hidalgo M, Siu LL, Nemunaitis J, Rizzo J, Hammond LA, et al. 2001. Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J. Clin. Oncol. 19 3267-79... 

More than the half of the known receptor tyrosine kinases have been repeatedly found in either mutated or overexpressed forms in human malignancies, including sporadic cancers. Most activating mutations lead to a ligand-independent, constitutive activation of the tyrosine kinase activity of the receptor. As outlined in Chapter 8, receptor tyrosine kinases normally exist in a repressed state and require ligand-induced autophosphorylation for activation. Oncogenic receptor tyrosine kinases often escape from this control and induce inappropriate activation of downstream signaling components that leads to enhanced cell proliferation and increased cell survival (review Blume-Jensen and Hunter, 2001). 

Westerhoff M, Faoro L, Loganathan S, et al. Immrmohisto-chemical (IHC) expression of c-Met receptor tyrosine kinase (c-Met) has prognostic significance and its activation is related to phosphorylated protein kinase Cff (p-PKC ff) in malignant mesothelioma (MM). Mod Pathol. 2008 21 353A. 

Yano S, Herbst RS, Shinohara H, et al. Treatment for malignant pleural eflusion of human lung adenocarcinoma by inhibition of vascular endothelial growth factor receptor tyrosine kinase phosphorylation. Clin Cancer Res 2000 6 957-965. 

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