Folate Receptors: A New Target to Kill Cancer Cells?

by Cara Tenenbaum

Numerous anti-cancer therapies aim to target a specific pathway, such as the vascular endothelial growth factor (VEGF) targeted by drugs like bevacizumab. Another potential targeted treatment is to block folate, a nutrient that cancer cells need to grow. Folate is a form of Vitamin B that is required for cell division. Some cells have folate receptors that grab folate and bring it into the cell. One type of folate receptor, folate receptor alpha (FRA), is over-expressed in many types of epithelial cancers, including ovarian. For this reason, targeting or taking advantage of the folate receptor is an emerging field in ovarian cancer research.

For more than 50 years we have known that folate is active in some types of cancer. In 1946, Dr. Sidney Farber found that giving folic acid to children with leukemia accelerated their cancer’s progress. The next year, he started using an anti-folate—a molecule that looked like folic acid but did not deliver any vitamins—as a therapy for children with this cancer. In 1948, Dr. Farber published a preliminary paper in the New England Journal of Medicine following the treatment of 16 patients and showing evidence that treatment with an anti-folate extended children’s lives.

Researchers are investigating two ways of using the folate receptor to kill ovarian cancer. One is to treat women with an antibody that binds tightly with FRA. The antibody acts like a flare, telling the body’s immune system which cells to attack and triggering the body’s immune system to kill the cancer cell. The second way is to attach a drug to something that looks like folic acid; the combined molecule delivers the drug through the FRA pathway much like a Trojan horse. These potential uses of the folate receptor could not only kill cancer cells, but do so in a targeted fashion that could greatly reduce the side effects of anti-cancer therapies.

Although ovarian cancer cells use folic acid for cell division, avoiding foods with folate will not cure or prevent cancer. Further, folate is necessary for normal cell function and is conserved by the body. Experts say that any folate ingested at all would first go to the folate receptors that are over-expressed—like ovarian cancer cells. Therefore decreasing dietary folate does not halt the progress of cancer.

Not only is targeting the folate receptor a potential pathway for cancer treatment, it opens up questions about combination therapies. For example, could we use a sequence or combination of drugs that targets multiple pathways and use more than one agent at the same time? Experts say multimodality treatment is not too far in the future. “We won World War II with the Army, Navy, Air Force, SEALS and other forces; we’re not going to cure someone of cancer with just one drug,” says Dr. Bart Kamen, a leading expert on folate receptors.

Two companies are developing folate receptor drugs for ovarian cancer: Morphotek (which is developing Farletuzemab) and Endocyte (which is developing EC145). Click here to learn more about clinical trials in ovarian cancer.

Thanks to Dr. Barton A. Kamen and to Siddhartha Mukherjee, whose work The Emperor of All Maladies discussed Dr. Farber’s discovery.