By Sue Rochman

Growth Factors: Jekyll and Hyde

These protein bosses can make cells go haywire, but they've also provided targets for new cancer patients

By Sue Rochman

But easier does not mean easy. It's been a long road from the identification of growth factors to the development of drugs that interrupt their work. However, there have been some groundbreaking achievements. Herceptin (trastuzumab) was approved by the U.S. Food and Drug Administration (FDA) in 1998 for women with metastatic breast cancer whose tumors are of a type called HER2-positive. Identified more than a decade before Herceptin's approval, HER2 is a member of the HER family of receptors. (HER stands for human epidermal growth factor receptor.) Women whose tumors are HER2-positive have cells that contain too many copies of the HER2 gene, which helps cells grow, divide and repair themselves. Cells with these excess genes create too many HER2 receptors on their surfaces.

As a result, explains Verma, "even if there is only a small amount of growth factor in circulation, because the cell has more receptors, it divides more" than it should. Herceptin works by blocking the growth factor's ability to talk to the receptor. It's as if the growth factor gets a busy signal when it tries to call. This, in turn, keeps the cell from dividing.

More recently, Herceptin has also been found to significantly reduce breast cancer recurrence in women with early-stage HER2-positive breast cancer. Studies are now ongoing to see if the drug may also be effective in treating ovarian, bladder, salivary gland and endometrial cancer by blocking the HER2 receptor on these types of cancer cells.

Vascular endothelial growth factor (VEGF) has also attracted significant attention from researchers. VEGF binds to and stimulates receptors on cells that line the blood vessels, called vascular endothelial cells, and this effect is responsible for the development of new blood vessels—a process called angiogenesis. "When cancer grows, it needs blood vessels to feed it," explains Verma. To ensure that it has these blood vessels, "cancer cells, or the cells around them, secrete VEGF." The drug Avastin (bevacizumab) blocks the VEGF growth factor from binding to the VEGF receptor. In 2004, the U.S. Food and Drug Administration approved it for patients with metastatic colorectal cancer. Studies are now testing Avastin's effectiveness in treating renal cell carcinoma, malignant melanoma, brain tumors, and breast, bladder, ovarian and pancreatic cancers.

In the future, other growth factors may also become targets for new therapies that take advantage of our increasingly intimate understanding of how cells function. Ittmann's lab, for example, is studying fibroblast growth factors, which belong to a family of proteins that oversee the growth of a number of different types of cells, and are important in prostate, bladder and other cancers. Meanwhile, epidemiologist Jing Ma, at Harvard Medical School, is among those who are studying insulin-like growth factor (IGF). Ma has found that high IGF levels in the blood increases an individual's risk of developing colon cancer and prostate cancer. This research could lead to new ways of controlling growth factors to prevent cancer from occurring.

"A lot of the excitement in the field has been in showing that different kinds of cancer have a strong dependence on certain types of growth factors," says Ittmann. "And if you can target that receptor using a [drug], then you have therapeutic potential." 

WANTED: MORE GROWTH FACTORS
Researchers' emphasis on keeping growth factors in check (see above article) might lead you to believe that you never want these receptors in overdrive. But that's not the case. There are times when people undergoing cancer treatment can benefit from an abundance of growth factors. The growth factor G-CSF, which is sold in synthetic forms under the names Neupogen (filgrastim) and Neulasta (pegfilgrastim), is given to patients during chemotherapy to stimulate the development of infection-fighting white blood cells. And patients take synthetic versions of the growth factor erythropoietin (EPO) to fight fatigue because it stimulates the development of red blood cells, which carry oxygen through the body. Right now, for treating cancer, says Amit Verma of the Albert Einstein College of Medicine in New York City, "These are two of the most important growth factors."  

–S.R.