Beyond VEGF: Targeting Tumor Growth and Angiogenesis via Alternative Mechanisms

  • James Christensen
  • Kenna Anderes
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 610)

Cancer is a multiplicity of diseases characterized by a range of molecular defects leading to unregulated, aberrant cell growth. Recent improvements in understanding the molecular basis of cancer progression, improved diagnostics, and the emergence of new classes of therapeutics have offered promise to better manage the disease. Chemotherapeutic agents that induce cytotoxicity by damaging DNA have been the mainstay of cancer treatment for many decades. Despite their effectiveness, there are a number of limitations, most notably a narrow therapeutic window due to lack of selectivity toward cancer cells. A new generation of chemotherapeutic agents commonly referred to as “targeted therapies” is emerging and aims to impart selectivity to cancer cells by exploiting molecular differences between normal and cancer cells. The best known examples of these new drugs are imatinib and erlotinib, both acting through inhibition of the tyrosine kinases (TKs) BCR-ABL and EGFR, respectively. Lessons learned from imatinib and erlotinib include the necessity for careful patient selection, (i.e., identification of the underlying molecular anomalies) to optimize the potential efficacy of targeted therapies. In this chapter, we describe two novel kinase targeted therapies with distinct mechanisms of action: checkpoint kinase 1 (Chk1) and c-Met kinase inhibitors. Inhibition of Chk1 represents a molecularly targeted approach to selectively enhance the cytotoxicity of DNA-damaging agents in tumor cells with intrinsic checkpoint defects (mutated p53) while minimizing toxicity in normal cells that have a checkpoint competent molecular phenotype (wild-type p53). In contrast, an extensive body of literature indicates that c-Met is one of the most frequently genetically altered or otherwise dysregulated RTKs in advanced cancers implicating it as a key target for therapeutic intervention.


Hepatocyte Growth Factor Anaplastic Large Cell Lymphoma Antitumor Efficacy Antiangiogenic Activity Human Umbilical Vascular Endothelial Cell 


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Copyright information

© Springer 2008

Authors and Affiliations

  • James Christensen
    • 1
  • Kenna Anderes
    • 1
  1. 1.Department of Cancer Biology, Pfizer Global Research and DevelopmentLa Jolla LaboratoriesLa Jolla

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