PARIS, France--Overexpression of growth factor receptors correlates with a poor prognosis in many malignancies, including breast, bladder, and lung cancer, and new evidence suggests that growth factor receptors may be an important target for anticancer therapy, John Mendelsohn, MD, said at the Fifth International Congress on Anti-Cancer Chemotherapy.
The rationale for this novel therapeutic approach, said Dr. Mendelsohn, of Memorial Sloan-Kettering Cancer Center, also stems from the observations that most cells require growth factors to proliferate, and that about one third of proto-oncogenes code for growth factors, their receptors, or biochemical steps in the signal transduction pathways activated by the receptors.
Moreover, he noted, transfection of growth factors into nonmalignant cells can cause these cells to behave in a malignant fashion. Thus, if the actions of growth factors on their receptors can be interrupted therapeutically, it may be possible to block cellular proliferation.
Growth factors may induce cellular proliferation, either through autocrine stimulation or through stimulation of adjacent cells, Dr. Mendelsohn told the conference audience. For example, he said, platelet-derived growth factor (PDGF) produced by breast cancer cells stimulates fibroblast PDGF receptors, causing the fibroblasts to produce IGF (insulin-like growth factor), which then in turn goes back and autostimulates the breast cancer cells.
To illustrate autostimulation of cells, he described how the portion of the epidermal growth factor (EGF) receptor that exists outside the cell membrane can be stimulated by EGF or by transforming growth factor-alpha (TGF-alpha), both of which are often produced by the same cell. The stimulated receptor then activates its intrinsic tyrosine kinase, leading to protein phosphorylation and, eventually, to cellular proliferation.
Dr. Mendelsohn and his colleagues have produced monoclonal antibodies that block the binding of EGF to its receptor, and thereby inhibit EGF- and TGF-alpha-induced activation of tyrosine kinase. "This is not immunotherapy--this is a drug that will block the enzyme tyrosine kinase," he stressed, pointing out that even antibody fragments that lack immune activity can still inhibit cellular growth.
Although very early administration of these monoclonal antibodies can completely inhibit human tumor growth in nude mice, well-established tumors are more resistant to cure. However, Dr. Mendelsohn said, in combination with such cytotoxic agents as platinum, doxorubicin(Drug information on doxorubicin), or paclitaxel(Drug information on paclitaxel) (Taxol), EGF receptor blockade can eliminate established tumors in xenograft models.