Anticancer therapeutics: "Addictive" targets, multi-targeted drugs, new drug combinations

The annual meeting of the American Association for Cancer Research (AACR) provided a panoramic view of new developments and trends in cancer research. In the area of new drug development, a recurrent theme was receptor tyrosine kinase (TK) inhibitors, with multi-targeted, small molecule inhibitors - highly potent against a family of receptors such as vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor (PDGFR) and the receptor tyrosine kinase KIT - taking centre stage. Several agents interfering with intracellular targets that are components of key oncogenic signaling pathways, such as RAF kinase, phosphatidylinositol 3-kinase (PI3K)/Akt or Src, are in preclinical and early clinical development. "Addictive" targets, such as the Bcr-Abl fusion protein in chronic myeloid leukemia (CML), are critical for maintaining the malignant phenotype and hence represent an Achilles' heel for selective drugs. Significantly, novel targeted therapeutics currently in clinical development do not generally lead to cures or long-term survival for most intractable cancers; resistance may eventually develop. Anti-metastatic agents and anti-adhesion drugs, which collectively act on tumor cell-stroma interactions (anti-stromal therapy), are also actively pursued. In addition, forms of cell death other than apoptosis - cellular senescence, cancer cell-specific cell-cycle processes and the hypoxic environment - are being explored in order to identify novel targets for more selective therapy. This report also highlights developments aimed at more safe and effective drug combinations. Evaluating drug combinations, and elucidating the rationale for combinations of old (cytotoxic) and new (biological) anticancer agents, are promising research areas and taxane-based combinations are presented as examples. The report is based on presentations at AACR 2005 and related publications of the first half of 2005.