Cancer is characterized by the unregulated autonomous growth of cells. Uncontrolled increased pro duction of active growth factors can be a cause of this condition, as can the overexpression of the cognate membrane receptors for the growth factor. In either case the downstream pathways leading to increased proliferation are activated. Thus, both growth factors and their receptors have become targets for drugs to rein in the uncontrolled growth of cancer cells.
Table 1 lists some of the drugs that have been developed to target specific growth factors or their receptors. It should be noted that this is just a limited illustrative list of such drugs, of which there are several-fold more in various stages of development. The purpose of the illustration is to underscore the importance of understanding the structures of the growth factors and their receptors; the pathways by which growth factors are synthesized and activated from latent forms; the mechanisms of receptor activation; and the downstream signaling pathways.
Table1. Cancer Drugs Targeting Growth Factors and Their Receptors
Because the majority of human epithelial cancers over express EGF or one of its receptors, the EGF receptors, EGFR and HER2, have been targets of monoclonal anti body drugs (denoted by the syllable mab in the name). Particularly in breast cancer, but in others as well, it is standard to test the cancer cells for overexpression of HER2, which is active in the absence of ligand and is the preferred dimerization partner of the family, and, if positive, to treat with a drug of the kind listed in Table 1.
Another common target is the inhibition of the tyrosine kinase activity of growth factor receptors. Examples of these for the EGF and FGF families are shown in Table 1; the names of these drugs often end in the syllable ib. Inhibition of a specific growth factor with an antisense oligonucleotide has been achieved in the case of TGFβ-2 mRNA in the treatment of glioblastoma.
The development and use of these important and promising drugs is hampered by the very complexity of the systems that are targeted. For example, since the growth factors have normal physiological functions, interference with these can lead to intolerable side effects. In some cases, such as TGFβ, the window of treatment may be limited because the target has growth controlling properties early in the oncogenic process but promotes metastatic disease later in the process. And, for reasons that are not understood, patients may become refractory to a given treatment whereupon the metastatic process continues. As our understanding of the growth factors, their receptors, and their roles in particular neoplasms deepens, these obstacles should be surmountable.
